RU2781643C2 - Thiophene derivative and its use - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to thiophene derivatives corresponding to the following formula (I):

,

where each symbol is such as defined in the claims, or its pharmaceutically acceptable salt, which have activity of suppression of TNF-α production and activity of inhibition of proliferation of hematological malignant cells, and it is suitable for the treatment of rheumatoid arthritis, Crohn’s disease, ulcerative colitis, and, in addition, hematological malignant tumor.

EFFECT: obtaining thiophene derivatives for the treatment of diseases.

24 cl, 2 tbl, 56 ex

Description

[Technical field]

[0001]

The present invention relates to the field of pharmaceuticals, in particular, to new thiophene derivatives having an activity of suppressing the production of TNF-α and an activity of inhibiting the growth of hematological malignant cells.

[Prior Art]

[0002]

Tumor necrosis factor-α (TNF-α) is an inflammatory cytokine released by cells of the immune system. Continuous and excessive production of TNF-α is known to cause tissue damage and various diseases (Non-Patent Document 1). Examples of pathological conditions involving TNF-α include many pathological conditions, including autoimmune diseases such as rheumatoid arthritis, Crohn's disease and ulcerative colitis.

[0003]

In view of the foregoing, compounds which inhibit the production of TNF-α are expected to be effective in the treatment of the aforementioned diseases, and various studies have been carried out.

[0004]

Therapeutic agents for rheumatoid arthritis, which is a representative autoimmune disease, are generally classified into the following three types.

[0005]

The first group of therapeutic agents are anti-inflammatory agents. Anti-inflammatory drugs work by reducing the pain and swelling associated with inflammation. Moreover, anti-inflammatory drugs are divided into non-steroidal anti-inflammatory drugs (NSAIDs) and steroids. Examples of NSAIDs include celecoxib, loxoprofen, indomethacin, and the like. While these agents immediately relieve swelling and pain caused by inflammation, they have little effect in suppressing the progression of rheumatism. On the other hand, steroids largely suppress inflammation and are effective against pain, swelling, and stiffness. However, long-term use of a high dose of steroids can cause the problem of opportunistic infection, osteoporosis, or arteriosclerosis.

[0006]

The second group of therapeutic agents are disease-modifying antirheumatic drugs (DMARDs). DMARDs act directly on immune disorders, suppress inflammation, and inhibit disease progression. On the other hand, there are problems such as no way to predict efficacy, slow onset of action, and high incidence of side effects, while efficacy varies greatly among individuals.

[0007]

The third group of therapeutic agents are biological agents. There are many biologics on the market, such as infliximab sold as REMICADE (registered trademark) and etanercept sold as ENBREL (registered trademark) (patent document 1). Biological agents show high efficiency, but their problem is that they are very expensive. In recent years, JAK inhibitors such as tofacitinib, sold as XELJANZ (registered trademark), which is a small molecule compound, have come on the market and are attracting attention because they show efficacy comparable to that of biological agents. However, there is a problem that the risk of serious infection increases in a dose-dependent manner, and the like. Thus, it is desirable to develop a new antirheumatic drug that can be administered orally and that has an effect comparable to that of biological agents.

[0008]

Hematological malignancy is a disease caused by malignancy of blood cells such as erythrocytes, leukocytes and platelets during differentiation. Among hematological tumors, multiple myeloma, malignant lymphoma and leukemia, which constitute a particularly large number of patients, are called the three main hematological malignancies.

[0009]

Multiple myeloma is a disease caused by malignancy of plasma cells that have differentiated and matured from B cells, which are leukocytes, a type of blood cell. In the medical treatment of multiple myeloma, the administration of protease inhibitors (bortezomib, carfilzomib, ixazomib) and immunomodulators (thalidomide, lenalidomide, pomalidomide) significantly improved the prognosis and ensured long-term survival (non-patent documents 2, 3). However, multiple myeloma is not a disease for which a cure is expected, and its main therapeutic goal is to prolong survival while maintaining the QOL of relapsed patients. In addition, the prognosis has been found to further improve with the use of two antibody drugs (erotuzumab, daratumumab) developed in recent years; however, the aggravation of the course of the disease is not prevented by the density (Non-Patent Document 4).

[0010]

Malignant lymphoma is a disease caused by malignancy of lymphocytes, which are white blood cells, a type of blood cell. Chemotherapy is still the mainstay of medical treatment for malignant lymphoma. Even though it is a hematological tumor that can be cured, cure rates vary greatly depending on the type of disease, and some malignant lymphomas are difficult to treat with chemotherapy (Non-Patent Document 5). For cases where chemotherapy cannot achieve a sufficient therapeutic effect, treatment with a molecular targeted drug alone or in combination with a chemotherapeutic agent may be attempted. For example, in B-cell non-Hodgkin's lymphoma, which has a CD20 positivity rate of 90% or more, the combined use of an anti-CD20 antibody drug, rituximab, and another drug has become the mainstay of therapy. As a specific example, the combined use of rituximab therapy and chemotherapy (eg, CHOP therapy) is recommended for patients with newly diagnosed diffuse large B-cell lymphoma, mantle cell lymphoma, or follicular lymphoma, and rituximab is the primary molecular targeted drug ( non-patent document 6).

[0011]

Other molecular targeted drugs for B-cell non-Hodgkin's lymphoma that are gaining attention include ibrutinib, which is a Bruton's tyrosine kinase (BTK) inhibitor, and lenalidomide, which is an immunomodulator. In particular, lenalidomide improves prognosis in patients with diffuse large B-cell lymphoma other than the germinal center B-cell type (GCB), but is less effective against diffuse large B-cell lymphoma of the GCB type, moreover, in the combination test with rituximab in patients with recurrent mantle cell lymphoma, the overall response rate was 56% with 44% non-responders. Thus, it is desirable to develop a new therapeutic agent effective against malignant lymphoma (Non-Patent Document 7).

[0012]

WO 2017/197051 (patent document 2) describes a compound having a glutarimide group. However, there is no specific description regarding the compound of the present invention having a thiophene ring.

[Bibliography]

[Patent Documents]

[0013]

Patent Document 1: National Publication of International Patent Application No. 2012-524071

patent document 2: WO 2017/197051

[non-patent documents]

[0014]

non-patent document 1: Yamazaki, Clinical Immunology, 27, 1270, 1995

non-patent document 2: Terui, Internal Medicine, Vol. 120, no. 4, page 875, 2017

non-patent document 3: Shibayama, Internal Medicine, Vol. 120, no. 4, page 881, 2017

non-patent document 4: Zhang, Internal Medicine, Vol. 120, no. 4, page 887, 2017

non-patent document 5: Suzumiya, The Journal of the Japanese Society of Internal Medicine, Volume 105, No. 9, page 1761, 2016

non-patent document 6: NCCN guideline Japanese version, non-Hodgkin's lymphoma, 2nd edition, 2015

non-patent document 7: Arora. m., Ther Adv Hematol, Vol. 7, no. 4, page 209, 2016.

[Summary of the Invention]

[Technical problem]

[0015]

An object of the present invention is to provide novel thiophene derivatives having an activity of suppressing TNF-α production and useful in the treatment of rheumatoid arthritis, Crohn's disease, ulcerative colitis or hematological malignancy, and medicaments containing the same.

[Solution]

[0016]

The present inventors have conducted rigorous studies in an attempt to solve the above problem, and have found that the compound according to the general formula (I) has an excellent TNF-α production suppression activity. In addition, they conducted various tests of its suitability as an anti-cancer drug and completed the present invention. Thus, the present invention relates to the following.

[0017]

[1] The compound corresponding to the general formula (I):

[0018]

[0019]

where:

R ₁ is hydrogen or halogen;

R in number m is at each occurrence independently halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy optionally having a substituent, C1-6 alkoxycarbonyl or C1-6 alkylcarbonyl, or

two Rs on adjacent ring carbons are bonded to each other to form, together with the carbons to which they are attached, a 5- or 6-membered ring containing 1-2 oxygen atoms; and

m is 0, 1, 2 or 3,

or a salt thereof (hereinafter sometimes also referred to as "the compound of the present invention").

[0020]

[2] The compound according to the above [1] or a salt thereof, wherein the compound corresponding to the general formula (I) is a compound corresponding to the following general formula (IA) or (IB):

[0021]

[0022]

[0023]

where:

R ₁ is hydrogen or halogen;

R ₂ is hydrogen, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, or C1-6 alkylcarbonyl;

R ₃ is hydrogen, halogen, C1-6 alkyl or C1-6 alkoxy, optionally having a substituent;

R ₄ is hydrogen, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, or C1-6 alkylcarbonyl;

R ₅ is hydrogen, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, or C1-6 alkylcarbonyl;

R ₆ is hydrogen, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, or C1-6 alkylcarbonyl, or

R ₅ and R ₆ are connected to each other to form, together with the carbon atoms to which they are attached, a 5- or 6-membered ring containing 1-2 oxygen atoms; and

R ₇ is hydrogen, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, or C1-6 alkylcarbonyl.

[3] The compound according to the above [2] or a salt thereof, wherein R ₁ is hydrogen or halogen;

R ₂ is hydrogen, halogen or C1-6 alkoxy;

R ₃ is hydrogen, halogen, C1-6 alkyl or C1-6 alkoxy, optionally having a substituent;

R ₄ is hydrogen, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, or C1-6 alkoxycarbonyl;

each of R ₅ and R ₆ is hydrogen, or

R ₅ and R ₆ are connected to each other to form, together with the carbon atoms to which they are attached, a 5- or 6-membered ring containing 1-2 oxygen atoms; and

R ₇ is hydrogen, halogen, C1-6 alkyl or C1-6 alkylcarbonyl.

[4] The compound according to any of the above [1]-[3] or a salt thereof, wherein C1-6 alkoxy optionally having a substituent for R and R ₃ is C1-6 chain alkoxy, C3-6 cycloalkoxy, or

alkoxy corresponding to the formula: -O-X—Y

where:

X is a linear or branched C1-6 alkylene; and

Y is C3-6 cycloalkyl, or pyridine, naphthalene or benzothiophene, each of which optionally has a substituent, or a substituent corresponding to the general formula (II):

[0024]

[0025]

Z represents hydrogen, C1-6 alkoxy, C1-6 alkoxymethyl, halogen, or a substituent corresponding to the following general formulas (III), (IV), (V) or (VI):

[0026]

[0027]

Z ₁ and Z ₂ are each independently hydrogen or C1-6 alkyl, or

Z ₁ and Z ₂ are connected to each other to form, together with the nitrogen atom to which they are attached, a 5- or 6-membered ring; and

n is 1 or 2

[0028]

[0029]

[0030]

.

.

[0031]

[5] The compound according to the above [4], wherein X is CH ₂ , CH(CH ₃ ) or CH ₂ CH ₂ , or a salt thereof.

[6] The compound according to any of the above [2]-[5], or its acid additive salt, where R ₁ represents hydrogen, iodine, bromine or chlorine;

R ₂ represents hydrogen, bromine or methoxy;

R ₃ is hydrogen, bromine, chlorine, methyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, cyclopentyloxy, cyclopropylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, benzyloxy, 1-phenylethoxy, pyridin-2-ylmethoxy, pyridin-3-ylmethoxy, pyridine- 4-ylmethoxy, benzo[b]thiophen-2-ylmethoxy, 4-methoxybenzyloxy, 4-(methoxymethyl)benzyloxy, 4-chlorobenzyloxy, 4-(pyrrolidin-1-ylmethyl)benzyloxy, 4-(piperidin-1-ylmethyl)benzyloxy , 4-[(dimethylamino)methyl]benzyloxy, 4-(2-morpholinoethyl)benzyloxy, 2-(morpholinomethyl)benzyloxy, 3-(morpholinomethyl)benzyloxy, 4-(morpholinomethyl)benzyloxy or 4-{[(2S,6R) -2,6-dimethylmorpholino]methyl}benzyloxy;

R ₄ is hydrogen, bromine, chlorine, methyl, hydroxymethyl, methoxy, ethoxy or methoxycarbonyl;

each of R ₅ and R ₆ is hydrogen, or

R ₅ and R ₆ are connected to each other to form, together with the carbon atoms to which they are attached, a 6-membered ring containing two oxygen atoms;

R ₇ represents hydrogen, chlorine, bromine, methyl or acetyl.

[0032]

[7] The compound according to any of the above [1]-[6], or a salt thereof, wherein the compound or salt is selected from the following

3-[4-(4-bromothiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione,

3-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,

3-[4-(thiophen-2-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,

3-[5-chloro-4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione,

3-[4-(5-methylthiophen-2-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione,

3-[4-(5-methylthiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione,

3-[4-(4-methylthiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione,

3-[4-(5-acetylthiophen-2-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione,

3-{4-[5-(hydroxymethyl)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidin-2,6-dione,

3-[4-(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6- dion,

3-[4-(5-chlorothiophen-2-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione,

3-[4-(5-bromothiophen-2-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,

3-[4-(2,5-dibromothiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione,

3-[4-(4-chlorothiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione,

3-[4-(4-Methoxy-5-methylthiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione,

methyl 4-[1-(2,6-dioxopiperidin-3-yl)-1H-1,2,3-triazol-4-yl]-3-methoxythiophene-2-carboxylate,

3-[4-(4-ethoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione,

3-[4-(2-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione,

3-[4-(4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione,

3-[4-(5-Methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione,

3-[4-(4-propoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione,

3-[4-(5-Chloro-4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione,

3-[4-(5-bromo-4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,

3-[4-(5-ethoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione,

3-[4-(4-butoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione,

3-[4-(4-isopropoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione,

3-{4-[4-(cyclopentyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidin-2,6-dione,

3-{4-[4-(cyclopropylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidin-2,6-dione,

3-{4-[4-(cyclopentylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione,

3-{4-[4-(cyclohexylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione,

3-{4-[4-(4-methoxybenzyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione,

3-{4-[4-(benzyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidin-2,6-dione,

3-{4-[4-(pyridin-4-ylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione,

3-{4-[4-(pyridin-2-ylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione,

3-{4-[4-(pyridin-3-ylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione,

3-(4-{4-[4-(morpholinomethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione,

3-(4-{4-[4-(methoxymethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione,

3-{4-[4-(4-{[(2S,6R)-2,6-dimethylmorpholino]methyl}benzyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl} piperidine-2,6-dione,

3-(4-{4-[3-(morpholinomethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione,

3-(4-{4-[2-(morpholinomethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione,

3-(4-{4-[4-(pyrrolidin-1-ylmethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidin-2,6-dione,

3-(4-{4-[4-(piperidin-1-ylmethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidin-2,6-dione,

3-{4-[4-(4-chlorobenzyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione,

3-{4-[4-(1-phenylethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione,

3-(4-{4-[4-(2-morpholinoethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione,

3-[4-(4-{4-[(dimethylamino)methyl]benzyloxy}thiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,

3-{4-[4-(benzo[b]thiophen-2-ylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidin-2,6-dione,

3-[5-bromo-4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione, and

3-[5-iodine-4-(4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione, and their acid addition salts.

[0033]

[8] The compound according to the above [2] or a salt thereof, wherein the compound corresponding to the general formula (I) is a compound corresponding to the following general formula (IA):

[0034]

[0035]

where:

R ₁ is hydrogen;

R ₂ is hydrogen;

R ₃ is hydrogen or C1-6 alkoxy optionally having a substituent; and

R ₄ is hydrogen, C1-6 alkoxy or halogen.

[9] The compound according to the above [8] or a salt thereof, wherein R ₃ is hydrogen, C1-6 alkoxy, or

alkoxy corresponding to the formula: -O-X—Y

where:

X is linear C1-6 alkylene; and

Y is a benzothiophene, pyridine or a substituent corresponding to the general formula (II):

[0036]

[0037]

Z is hydrogen, C1-6 alkoxymethyl, or a substituent according to the following general formulas (III), (IV), (V) or (VI):

[0038]

[0039]

each Z ₁ and Z ₂ is C1-6 alkyl, or

Z ₁ and Z ₂ are connected to each other to form, together with the nitrogen atom to which they are attached, a 5- or 6-membered ring; and

n is 1 or 2;

[0040]

[0041]

[0042]

, и

, and

[0043]

R ₄ is hydrogen, C1-6 alkoxy or halogen.

[10] A compound according to any of the above [1]-[9], or a salt thereof, wherein the compound or salt is selected from the following:

3-[4-(5-Methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione,

3-[4-(5-bromo-4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,

3-[4-(4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione,

3-{4-[4-(benzyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidin-2,6-dione,

3-(4-{4-[4-(methoxymethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione,

3-{4-[4-(4-{[(2S,6R)-2,6-dimethylmorpholino]methyl}benzyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl} piperidine-2,6-dione,

3-(4-{4-[4-(pyrrolidin-1-ylmethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidin-2,6-dione,

3-(4-{4-[4-(piperidin-1-ylmethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidin-2,6-dione,

3-(4-{4-[4-(2-morpholinoethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione,

3-[4-(4-{4-[(dimethylamino)methyl]benzyloxy}thiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione, and

3-{4-[4-(benzo[b]thiophen-2-ylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione and their acidic - additive salts.

[11] The compound according to any of the above [1]-[9], or a salt thereof, wherein the compound or salt is selected from the following:

3-[4-(5-Methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione,

3-[4-(4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione,

3-(4-{4-[4-(methoxymethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione,

3-{4-[4-(4-{[(2S,6R)-2,6-dimethylmorpholino]methyl}benzyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl} piperidine-2,6-dione,

3-(4-{4-[4-(piperidin-1-ylmethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidin-2,6-dione, and their acid addition salts.

[0044]

[12] A drug containing the compound according to the above [1] or a salt thereof as an active ingredient.

[13] The drug according to the above [12], wherein the drug is an agent that suppresses the production of TNF-α.

[14] The drug according to the above [12], wherein the drug is a prophylactic or therapeutic agent against an inflammatory disease, an autoimmune disease, or a hematological malignancy.

[0045]

[15] A pharmaceutical composition containing a compound according to the above [1] or a salt thereof as an active ingredient together with a pharmaceutically acceptable carrier.

[16] The pharmaceutical composition according to the above [15], wherein the composition is an agent that suppresses the production of TNF-α.

[17] The pharmaceutical composition according to the above [15], wherein the composition is a prophylactic or therapeutic agent against an inflammatory disease, an autoimmune disease, or a hematological malignancy.

[0046]

[18] A method for suppressing TNF-α production, comprising administering an effective amount of a compound according to the above [1] or a salt thereof to a mammal.

[19] A method for preventing or treating an inflammatory disease, an autoimmune disease, or a hematological malignancy, comprising administering a prophylactically or therapeutically effective amount of a compound according to the above [1] or a salt thereof to a mammal in need of its administration.

[0047]

[20] The compound according to the above [1] or a salt thereof, for use in the prevention or treatment of an inflammatory disease, an autoimmune disease, or a hematological malignancy.

[0048]

[21] The use of the compound according to the above [1] or a salt thereof for the preparation of a medicament.

[22] The use of the compound according to the above [1] or a salt thereof for the preparation of a medicament for the prevention or treatment of an inflammatory disease, an autoimmune disease, or a hematological malignancy.

[0049]

[23] The drug according to the above [14], the pharmaceutical composition according to the above [17], the method according to the above [19], the compound or salt thereof according to the above [20], or the use according to the above [22], wherein the autoimmune disease is rheumatoid arthritis, Crohn's disease or ulcerative colitis.

[24] The drug according to the above [14], the pharmaceutical composition according to the above [17], the method according to the above [19], the compound or salt thereof according to the above [20], or the use according to the above [22], wherein the hematological malignancy is leukemia , malignant lymphoma, or multiple myeloma.

[25] The drug according to the above [14], the pharmaceutical composition according to the above [17], the method according to the above [19], the compound or salt thereof according to the above [20], or the use according to the above [22], wherein the hematological malignancy is a multiple myeloma.

[26] The drug according to the above [14], the pharmaceutical composition according to the above [17], the method according to the above [19], the compound or salt thereof according to the above [20], or the use according to the above [22], wherein the hematological malignancy is a malignant lymphoma.

[27] The drug according to the above [14], the pharmaceutical composition according to the above [17], the method according to the above [19], the compound or salt thereof according to the above [20], or the use according to the above [22], wherein the hematological malignancy is leukemia .

[28] The drug according to the above [26], the pharmaceutical composition according to the above [26], the method according to the above [26], the compound or salt thereof according to the above [26], or the use according to the above [26], wherein the malignant lymphoma is non-Hodgkin's lymphoma .

[29] The drug according to the above [28], the pharmaceutical composition according to the above [28], the method according to the above [28], the compound or salt thereof according to the above [28], or the use according to the above [28], wherein non-Hodgkin's lymphoma is a neoplasm from lymphoid progenitors or neoplasms from mature B cells.

[Advantageous Effects of the Invention]

[0050]

According to the present invention, novel thiophene derivatives are provided useful for the prevention or treatment of inflammatory diseases such as rheumatoid arthritis, Crohn's disease, ulcerative colitis and the like, autoimmune diseases, and hematological malignancies such as multiple myeloma, malignant lymphoma, leukemia and the like, etc.

[Description of Embodiments]

[0051]

[Compound of the present invention]

The present invention is explained in detail below.

[0052]

The definition of each group used in the present description, detailed below. Unless otherwise specified, each group has the following definition.

[0053]

The salt of the compound of the present invention includes an acid addition salt, a base salt, an amino acid salt, and the like. Examples of the acid addition salt include salts with inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid and the like, salts with organic acids such as gluconic acid, tartaric acid, maleic acid, fumaric acid, succinic acid, malic acid, citric acid, mandelic acid, acetic acid, methanesulfonic acid and the like, and the like. Examples of base salts include alkali metal salts such as sodium, potassium and the like, alkaline earth metal salts such as calcium and the like, and the like. Examples of salts with amino acids include salts with amino acids such as glycine, lysine, arginine, ornithine, glutamic acid, aspartic acid, and the like and the like. The specific examples mentioned above are non-limiting. Among them, acid addition salt is preferable. When the compound of the present invention is used as a medicine, a pharmaceutically acceptable salt is particularly preferred.

[0054]

In the compound of the present invention, the halogen is fluorine, chlorine, bromine or iodine.

[0055]

In the compound of the present invention, C1-6 alkyl is, for example, a linear or branched alkyl group having 1 to 6 carbon atoms (hereinafter sometimes referred to as "C1-6 chain alkyl") or a cyclic alkyl group having 3 to 6 carbon atoms (hereinafter sometimes referred to as "C3-6 cycloalkyl") such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl , 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, and it optionally has a substituent. Preferably it is C1-4 alkyl or C3-6 cycloalkyl.

[0056]

In the compound of the present invention, C1-6 hydroxyalkyl is the aforementioned C1-6 alkyl substituted with one or more hydroxy groups. As a rule, it is substituted with 1-3 hydroxy groups, preferably substituted with one hydroxy group. For example, it is CH ₂ OH, CH ₂ CH ₂ OH, CH ₂ CH ₂ CH ₂ OH, CH(OH)CH ₂ OH, CH(CH ₃ )OH, CH(CH ₂ OH) ₂ and the like. , optionally having a substitute. Preferably it is C1-4 hydroxy alkyl.

[0057]

In the compound of the present invention, C1-6 alkoxy is, for example, a linear or branched alkoxy group having 1 to 6 carbon atoms (hereinafter sometimes referred to as "C1-6 chain alkoxy") or a cyclic alkoxy group having 3 to 6 carbon atoms. carbon (hereinafter sometimes referred to as "C3-6 cycloalkoxy") such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, etc. .p., and optionally has a substituent. Preferably it is a C1-4 or C3-6 cycloalkoxy alkoxy.

[0058]

In the compound of the present invention, C1-6 alkylcarbonyl is a carbonyl group substituted with a C1-6 alkyl group. For example, it is an alkylcarbonyl wherein the alkyl moiety is a linear or branched alkyl having 1-6 carbon atoms, such as methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, neopentylcarbonyl, hexylcarbonyl, and the like, and optionally has a substituent. Preferably it is C1-4 alkylcarbonyl.

[0059]

In the compound of the present invention, C1-6 alkoxycarbonyl is a carbonyl group substituted with a C1-6 alkoxy group. It is, for example, an alkoxycarbonyl group, where the alkoxy moiety is a linear or branched alkoxy having 1 to 6 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl and the like, and optionally has a substituent. Preferably it is C1-4 alkoxycarbonyl.

[0060]

In the compound of the present invention, C3-6 cycloalkyl is, for example, a cyclic alkyl group having 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, and optionally has a substituent.

[0061]

In the compound of the present invention, C3-6 cycloalkoxy is, for example, a cyclic alkoxy group having 3 to 6 carbon atoms such as cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like, and optionally has a substituent.

[0062]

In the compound of the present invention, C1-6 alkylene is, for example, a divalent group which can be formed by removing one hydrogen atom from the groups exemplified by the above C1-6 alkyl, and optionally has a substituent. Preferably it is a linear or branched C1-6 alkylene, more preferably a linear or branched C1-4 alkylene.

[0063]

"Optionally has a substituent" means that a substituent may be absent or one or more substituents may be present. An example of the presence of a substituent is when R ₃ in the above general formula (IA) is C1-6 alkoxy substituted with at least one (preferably 1-3) substituents of the above general formula (II) in a substitutable position(s). Other substituents may be appropriately selected by one of ordinary skill in the art from halo, hydroxy, and the like.

[0064]

Each character in the compound corresponding to the general formula (I) is explained below.

R ₁ is hydrogen or halogen (preferably chlorine, bromine, iodine).

R in number m is in each case independently halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, optionally having a substituent, C1-6 alkoxycarbonyl or C1-6 alkylcarbonyl, or two Rs on adjacent carbon atoms of the ring connected to each other with the other to form, together with the carbon atoms to which they are attached, a 5- or 6-membered ring containing 1-2 oxygen atoms and m is 0, 1, 2 or 3.

[0065]

Preferably, R number of m in each case independently represents

halogen (eg chlorine, bromine);

alkyl chain C1-6, more preferably alkyl chain C1-4 (for example, methyl);

C1-6 hydroxyalkyl, more preferably C1-4 hydroxy alkyl (eg hydroxymethyl);

C1-6 alkoxy, more preferably C1-4 alkoxy (eg methoxy, ethoxy, propoxy, isopropoxy, butoxy);

C3-6 cycloalkoxy (eg cyclopentyloxy);

alkoxy corresponding to the formula: -O-X—Y

where:

X is a linear or branched C1-6 alkylene, more preferably a linear or branched C1-4 alkylene (eg methylene, methylmethylene); and

Y is C3-6 cycloalkyl (eg cyclopropyl, cyclopentyl, cyclohexyl),

or pyridine, naphthalene or benzothiophene, each of which optionally has a substituent, preferably pyridine, naphthalene or benzothiophene, more preferably pyridine or benzothiophene, or a substituent corresponding to the general formula (II):

[0066]

[0067]

Z is hydrogen, C1-6 alkoxy, preferably C1-4 alkoxy (e.g. methoxy), C1-6 alkoxymethyl, preferably C1-4 alkoxymethyl (e.g. methoxymethyl), halogen (e.g. chlorine), or a substituent corresponding to the following general formulas (III), (IV), (V) or (VI):

[0068]

[0069]

Z ₁ and Z ₂ are each independently hydrogen or C1-6 alkyl, preferably hydrogen or C1-6 alkyl, more preferably C1-4 alkyl (eg methyl); or

Z ₁ and Z ₂ are bonded to each other to form, together with the nitrogen atom to which they are attached, a 5- or 6-membered ring (preferably a saturated 5- or 6-membered ring (eg pyrrolidine ring, piperidine ring); and

n is 1 or 2, preferably 1.

[0070]

[0071]

[0072]

;

;

[0073]

C1-6 alkoxycarbonyl, more preferably C1-4 alkoxycarbonyl (eg methoxycarbonyl);

C1-6 chain alkylcarbonyl, more preferably C1-4 chain alkylcarbonyl (eg acetyl); or

two Rs on adjacent ring carbons are bonded to each other to form, together with the carbons to which they are attached, a saturated 6-membered ring containing 2 oxygen atoms, more preferably a 6-membered ring containing OCH ₂ CH ₂ O (e.g. , 1,4-dioxane ring).

[0074]

Each symbol in a compound corresponding to the general formula (IA) or (IB) is explained below.

[0075]

R ₁ is hydrogen or halogen;

R ₂ is hydrogen, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, or C1-6 alkylcarbonyl;

R ₃ is hydrogen, halogen, C1-6 alkyl or C1-6 alkoxy, optionally having a substituent;

R ₄ is hydrogen, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, or C1-6 alkylcarbonyl;

R ₅ is hydrogen, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, or C1-6 alkylcarbonyl;

R ₆ is hydrogen, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, or C1-6 alkylcarbonyl, or

R ₅ and R ₆ are connected to each other to form, together with the carbon atoms to which they are attached, a 5- or 6-membered ring containing 1-2 oxygen atoms; and

R ₇ is hydrogen, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, or C1-6 alkylcarbonyl.

[0076]

In each of the above symbols, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkoxy optionally having a substituent, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl, and a 5- or 6-membered ring, containing 1-2 oxygen atoms formed by R ₅ and R ₆ connected to each other together with the carbon atoms to which they are attached may be as explained for the above-mentioned compound corresponding to the general formula (I).

[0077]

Preferred embodiments of each of the above symbols are explained below.

[0078]

R ₁ preferably represents hydrogen, chlorine, bromine or iodine.

[0079]

R ₂ is preferably hydrogen, halogen or C1-6 alkoxy. More preferably, it is hydrogen, halogen or C1-4 alkoxy, even more preferably hydrogen, bromine or methoxy.

[0080]

R ₃ is preferably hydrogen, halogen, C1-6 alkyl or C1-6 alkoxy, optionally having a substituent. As the halogen, bromine or chlorine is preferred. As C1-6 alkyl, C1-4 alkyl is preferred, and methyl is more preferred. C1-6 alkoxy optionally having a substituent is preferably C1-6 chain alkoxy, C3-6 cycloalkoxy or alkoxy corresponding to the formula: -OX-Y.

[0081]

As "C1-6 alkoxy" for R ₃ , preferred is C1-4 alkoxy, and more preferred is methoxy, ethoxy, propoxy, isopropoxy or butoxy.

[0082]

As "C3-6 cycloalkoxy" for R ₃ , cyclopentyloxy is preferred.

[0083]

In "alkoxy corresponding to the formula: -OX-Y" for R ₃ X is a linear or branched C1-6 alkylene. Y is C3-6 cycloalkyl, or pyridine, naphthalene, or benzothiophene, each of which optionally has a substituent, or a substituent corresponding to the following formula (II):

[0084]

.

.

[0085]

"Linear or branched C1-6 alkylene" for X is preferably linear or branched C1-4 alkylene, more preferably methylene(-CH ₂ -) or methylmethylene(-CH(CH ₃ )-), even more preferably methylene(-CH _2- ).

"C3-6 cycloalkyl" for Y is preferably cyclopropyl, cyclopentyl or cyclohexyl.

"Pyridine, naphthalene or benzothiophene, each of which optionally has a substituent" for Y is preferably pyridine, naphthalene or benzothiophene, more preferably pyridine or benzothiophene.

In the "substituent corresponding to the general formula (II)" for Y, Z is hydrogen, C1-6 alkoxy, C1-6 alkoxymethyl, halogen, or a substituent corresponding to the following general formulas (III), (IV), (V) or (VI):

[0086]

[0087]

[0088]

[0089]

.

.

[0090]

The C1-6 alkoxy for Z is preferably C1-6 chain alkoxy, more preferably C1-4 chain alkoxy, most preferably methoxy.

[0091]

The C1-6 alkoxymethyl for Z is preferably C1-6 alkoxymethyl, more preferably C1-4 alkoxymethyl, most preferably methoxymethyl.

[0092]

The halogen for Z is preferably chlorine, bromine, iodine, more preferably chlorine.

[0093]

In the substituent corresponding to the general formula (III),

Z ₁ and Z ₂ are each independently hydrogen or C1-6 alkyl, preferably hydrogen or C1-6 alkyl, more preferably C1-4 alkyl, most preferably methyl; or

Z ₁ and Z ₂ are connected to each other to form together with the nitrogen atom to which they are attached, a 5- or 6-membered ring, preferably a saturated 5- or 6-membered ring, more preferably a pyrrolidine ring or a piperidine ring; and

n is 1 or 2, more preferably 1.

[0094]

The most preferred "alkoxy corresponding to the formula: -O-X-Y," is, for example, cyclopropylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, benzyloxy, phenylethoxy (particularly preferably 1-phenylethoxy), methoxybenzyloxy (especially preferably 4-methoxybenzyloxy), methoxymethylbenzyloxy (especially preferably 4 -(methoxymethyl)benzyloxy), chlorobenzyloxy (particularly preferred 4-chlorobenzyloxy), (pyrrolidin-1-ylmethyl)benzyloxy (particularly preferred 4-(pyrrolidin-1-ylmethyl)benzyloxy), (piperidin-1-ylmethyl)benzyloxy (particularly preferred 4-(piperidin-1-ylmethyl)benzyloxy), [(dimethylamino)methyl]benzyloxy (especially preferably 4-[(dimethylamino)methyl]benzyloxy), morpholinoethylbenzyloxy (especially preferably 4-(2-morpholinoethyl)benzyloxy), morpholinomethylbenzyloxy (especially preferably 2-(morpholinomethyl)benzyloxy, 3-(morpholinomethyl)benzyloxy, 4-(morpholinomethyl)benzyloxy) or 2,6-dimethylmorpholinomethylbenzyloxy (especially preferably 4-{[ (2S,6R)-2,6-dimethylmorpholino]methyl}benzyloxy).

[0095]

R ₄ is preferably hydrogen, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy or C1-6 alkoxycarbonyl.

[0096]

The halogen for R ₄ is more preferably bromine or chlorine.

[0097]

The C1-6 chain alkyl for R ₄ is more preferably C1-4 chain alkyl, most preferably methyl.

[0098]

The C1-6 hydroxyalkyl for R ₄ is more preferably C1-4 hydroxy alkyl, most preferably hydroxymethyl.

[0099]

The C1-6 chain alkoxy for R ₄ is more preferably a C1-4 chain alkoxy, most preferably methoxy or ethoxy.

[0100]

The C1-6 alkoxycarbonyl for R ₄ is more preferably a C1-4 alkoxycarbonyl, most preferably methoxycarbonyl.

[0101]

R ₅ and R ₆ preferably each independently represent hydrogen, or

R ₅ and R ₆ are connected to each other to form, together with the carbon atoms to which they are attached, a 5- or 6-membered ring containing 1-2 oxygen atoms. A 5- or 6-membered ring containing 1-2 oxygen atoms is preferably a saturated 6-membered ring containing two oxygen atoms, more preferably a 6-membered ring containing OCH ₂ CH ₂ O, most preferably a 1,4- dioxane.

[0102]

R ₇ is preferably hydrogen, halogen, C1-6 alkyl or C1-6 alkylcarbonyl, more preferably hydrogen, halogen, C1-4 alkyl or C1-4 alkylcarbonyl, most preferably hydrogen, bromine, chlorine, methyl or acetyl.

[0103]

Specific preferred examples of the compound corresponding to the following formula (I) include the following compounds.

[0104]

[0105]

[Compound I-1]

Compound (I), where R ₁ represents hydrogen or halogen;

R of m is at each occurrence independently halogen, C1-6 alkyl, C1-6 hydroxyalkyl,

alkoxy chain C1-6, C3-6 cycloalkoxy,

alkoxy corresponding to the formula: -O-X—Y

where:

X is a linear or branched C1-6 alkylene; and

Y is C3-6 cycloalkyl, pyridine, naphthalene or benzothiophene, or a substituent corresponding to the general formula (II):

[0106]

,

,

[0107]

Z represents hydrogen, C1-6 alkoxy, C1-6 alkoxymethyl, halogen or a substituent corresponding to the following general formulas (III), (IV), (V) or (VI):

[0108]

,

,

[0109]

Z ₁ and Z ₂ are each independently hydrogen or C1-6 alkyl; or

Z ₁ and Z ₂ are connected to each other to form, together with the nitrogen atom connected to them, a saturated 5 - or 6-membered ring; and

n is 1 or 2,

[0110]

[0111]

[0112]

;

;

[0113]

C1-6 chain alkoxycarbonyl or C1-6 chain alkylcarbonyl, or

two R's on adjacent carbon atoms of the ring are bonded to each other to form, together with the carbon atoms to which they are attached, a saturated 6-membered ring containing 2 oxygen atoms; and

m is 0, 1, 2, or 3.

[0114]

[Compound I-2]

Compound (I) where R ₁ represents hydrogen;

R of m is in each case independently halogen,

alkoxy with C1-6 chain,

alkoxy corresponding to the formula: -O-X—Y

where:

X is linear C1-6 alkylene; and

Y is a benzothiophene, pyridine or a substituent corresponding to the general formula (II):

[0115]

[0116]

Z is hydrogen, C1-6 alkoxymethyl or a substituent corresponding to the following formulas (III), (IV), (V) or (VI):

[0117]

[0118]

each of Z ₁ and Z ₂ is C1-6 alkyl; or

Z ₁ and Z ₂ are connected to each other to form, together with the nitrogen atom to which they are attached, a 5- or 6-membered ring; and

n is 1 or 2

[0119]

[0120]

[0121]

; и

; and

[0122]

m is 0, 1, or 2.

[0123]

In another embodiment, specific preferred examples of compound (I) include compound (IA) and compound (IB) corresponding to the following formulas:

[0124]

[0125]

where

R ₁ is hydrogen or halogen;

R ₂ is hydrogen, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, or C1-6 alkylcarbonyl;

R ₃ is hydrogen, halogen, C1-6 alkyl or C1-6 alkoxy, optionally having a substituent;

R ₄ is hydrogen, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, or C1-6 alkylcarbonyl;

R ₅ is hydrogen, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, or C1-6 alkylcarbonyl;

R ₆ is hydrogen, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, or C1-6 alkylcarbonyl, or

R ₅ and R ₆ are connected to each other to form, together with the carbon atoms to which they are attached, a 5- or 6-membered ring containing 1-2 oxygen atoms; and

R ₇ is hydrogen, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, or C1-6 alkylcarbonyl.

[0126]

Specific preferred examples of compounds (IA) and (IB) include the following compounds.

[0127]

[Compound (IA)-1] and [Compound (IB)-1]

Compound (IA) and compound (IB) wherein R ₃ is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, or

alkoxy corresponding to the formula: -O-X—Y

where:

X is a linear or branched C1-6 alkylene; and

Y is C3-6 cycloalkyl, or pyridine, naphthalene or benzothiophene, each of which optionally has a substituent (more preferably pyridine, naphthalene or benzothiophene) or a substituent corresponding to the general formula (II):

[0128]

[0129]

Z represents hydrogen, C1-6 alkoxy, C1-6 alkoxymethyl, halogen or a substituent corresponding to the following general formulas (III), (IV), (V) or (VI):

[0130]

[0131]

Z ₁ and Z ₂ are each independently hydrogen or C1-6 alkyl, or

Z ₁ and Z ₂ are connected to each other to form, together with the nitrogen atom to which they are attached, a 5- or 6-membered ring; and

n is 1 or 2

[0132]

[0133]

[0134]

.

.

[0135]

[0136]

[Compound (IA)-2] and [Compound (IB)-2]

Connection (IA) and connection (IB), where R ₁ represents hydrogen or halogen;

R ₂ is hydrogen, halogen, or C1-6 alkoxy;

R ₃ is hydrogen, halogen, C1-6 alkyl or C1-6 alkoxy, optionally having a substituent;

R ₄ is hydrogen, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, or C1-6 alkoxycarbonyl;

each of R ₅ and R ₆ is hydrogen, or

R ₅ and R ₆ are connected to each other to form, together with the carbon atoms to which they are attached, a 5- or 6-membered ring containing 1-2 oxygen atoms; and

R ₇ is hydrogen, halogen, C1-6 alkyl or C1-6 alkylcarbonyl.

[0137]

[Compound (IA)-3] and [Compound (IB)-3]

Connection (IA) and connection (IB), where R ₁ represents hydrogen or halogen;

R ₂ is hydrogen, halogen or C1-6 alkoxy;

R ₃ is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkoxy, or

alkoxy corresponding to the formula: -O-X—Y

where:

X is a linear or branched C1-6 alkylene; and

Y is C3-6 cycloalkyl, pyridine, benzothiophene, or

substituent corresponding to the general formula (II):

[0138]

[0139]

Z represents hydrogen, C1-6 alkoxy, C1-6 alkoxymethyl, halogen or a substituent corresponding to the following general formulas (III), (IV), (V) or (VI):

[0140]

[0141]

Z ₁ and Z ₂ are each independently C1-6 alkyl; or

Z ₁ and Z ₂ are connected to each other to form, together with the nitrogen atom to which they are attached, a 5- or 6-membered ring; and

n is 1 or 2

[0142]

[0143]

[0144]

;

;

[0145]

R ₄ is hydrogen, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy or C1-6 alkoxycarbonyl;

each of R ₅ and R ₆ is hydrogen, or

R ₅ and R ₆ are connected to each other to form, together with the carbon atoms to which they are attached, a 5- or 6-membered ring containing 1-2 oxygen atoms; and

R ₇ is hydrogen, halo, C1-6 alkyl, or C1-6 alkylcarbonyl.

[0146]

[Compound (IA)-4]

Connection (IA), where R ₁ represents hydrogen;

R ₂ is hydrogen;

R ₃ is hydrogen, C1-6 alkoxy, or

alkoxy corresponding to the formula: -O-X—Y

where:

X is linear C1-6 alkylene; and

Y is a benzothiophene, pyridine or a substituent corresponding to the general formula (II):

[0147]

[0148]

Z represents hydrogen, C1-6 alkoxymethyl or a substituent corresponding to the following general formulas (III), (IV), (V) or (VI):

[0149]

[0150]

Z ₁ and Z ₂ are each independently C1-6 alkyl, or

Z ₁ and Z ₂ are connected to each other to form, together with the nitrogen atom to which they are attached, a 5- or 6-membered ring; and

n is 1 or 2

[0151]

[0152]

[0153]

; и

; and

[0154]

R ₄ is hydrogen, C1-6 alkoxy or halogen.

[0155]

[Method for producing the compound of the present invention]

The production method of the compound of the present invention is explained below.

[0156]

Each of the starting materials and reagents used in the following production methods and the resulting compounds can form a salt. Examples of such a salt include salts similar to the salt of the aforementioned compound of the present invention.

When the resulting compound is a free compound, it can be converted to the desired salt in a manner known per se. On the contrary, when the obtained compound of the present invention in each step is a salt, it can be converted into a free form or other type of desired salt in a manner known per se.

[0157]

While the production method of the compound of the present invention is not particularly limited, the compound, for example, can be obtained by subjecting the following compounds (VII) and (VIII) to an addition cyclization reaction to form a triazole ring.

[0158]

[0159] where R, R ₁ and m are as defined above.

[0160]

The reaction can be carried out by reacting the compound (VII) and the compound (VIII) in a dissolved or suspended state using a suitable solvent which does not adversely affect the reaction. Examples of such a suitable solvent include ether (eg, tetrahydrofuran, etc.), acetonitrile, alcohol (eg, t-butyl alcohol, etc.), water, and the like.

[0161]

The reaction can also be carried out in the presence of a suitable catalyst. Examples of such a catalyst include copper compounds (eg, copper(I) iodide, copper(II) acetate, copper(II) sulfate), ruthenium compounds (eg, chloro(pentamethylcyclopentadienyl)(cyclooctadiene)ruthenium(II)) and the like.

[0162]

While the reaction temperature is not particularly limited, the reaction, for example, can be carried out at a temperature from room temperature to heating.

[0163]

Those skilled in the art can define various conditions for the above reaction as appropriate.

[0164]

When the compound (VII) or compound (VIII) used as a starting compound in the production method of the present invention is commercially available, a commercially available product can be used, or it can be appropriately obtained from a known compound by a substantially known method, the method described in the "Examples" section below, or in a similar way.

[0165]

The compound of the present invention may be a crystal. The crystal of the compound of the present invention can be obtained by crystallizing the compound of the present invention using an essentially known crystallization method. Examples of the crystallization method include a solution crystallization method, a steam crystallization method, a molten mold crystallization method, and the like. Moreover, the compound of the present invention may be a pharmaceutically acceptable co-crystal or salt of the co-crystal. In the context of the present invention, co-crystal or co-crystal salt means a crystalline substance composed of two or more unique solids at room temperature, each of which has different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, stability, etc.). d.). A co-crystal or co-crystal salt can be obtained by a co-crystallization method known per se.

[0166]

The compound of the present invention may be any of a hydrate, non-hydrate, solvate, and non-solvate.

[0167]

[Use of the compound of the present invention]

The compound of the present invention has an excellent activity of suppressing the production of TNF-α and an activity of inhibiting the growth of hematological malignant cells, and thus is suitable, for example, as a safe drug based on these activities. The drug of the present invention containing the compound of the present invention is expected to exhibit low toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity, cardiotoxicity, carcinogenicity, etc.), and can be used as a prophylactic or therapeutic agent. against, for example, an inflammatory disease, an autoimmune disease, a hematological malignancy, and the like. in mammals (eg, mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, human, etc.).

[0168]

Examples of "inflammatory disease, autoimmune disease" include rheumatoid arthritis, Crohn's disease, multiple sclerosis, ulcerative colitis, systemic lupus erythematosus, erythema nodosum, osteoarthritis, gouty arthritis, rheumatoid spondylitis, autoimmune diabetes, and the like.

[0169]

Examples of "hematological cancer" include leukemia, lymphoma malignancy, multiple myeloma, and the like. Leukemia is classified into, but not limited to, acute leukemia and chronic leukemia. Acute leukemia includes, but is not limited to, acute myeloid leukemia, acute lymphocytic leukemia/lymphoblastic lymphoma, and acute promyelocytic leukemia. Chronic leukemia includes, but is not limited to, chronic myeloid leukemia, chronic lymphocytic leukemia/small lymphocytic lymphoma. Malignant lymphoma is classified into Hodgkin's lymphoma and non-Hodgkin's lymphoma. Hodgkin's lymphoma is further classified into classical Hodgkin's lymphoma and lymphoid-predominant nodular Hodgkin's lymphoma. Non-Hodgkin's lymphoma is further classified into neoplasms from lymphoid progenitors, neoplasms from mature B cells, and neoplasms from mature T/NK cells. Neoplasm from lymphoid progenitors is classified into B-cell lymphoblastic leukemia/lymphoma, T-cell lymphoblastic leukemia/lymphoma. Mature B cell neoplasm includes, but is not limited to, chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular lymphoma, MALT lymphoma, lymphoplasmic lymphoma, mantle cell lymphoma, diffuse large B cell lymphoma, Burkitt's lymphoma, and the like. Mature T/NK cell neoplasm includes, but is not limited to, peripheral T-cell lymphoma, adult T-cell leukemia/lymphoma, extranodal NK/T-cell lymphoma, extranodal nasal-type NK/T-cell lymphoma, mycosis fungoides, Cesari syndrome, etc.

[0170]

As used herein, "prevention" includes preventing the onset of a disease (all or one or more pathological conditions) and slowing the onset of the disease. "Prophylactically effective amount" refers to the dose of the compounds of the present invention, which is sufficient to achieve the goal. "Treatment" includes curing a disease (all or one or more of the disease states), improving the disease, and inhibiting the progression of the severity of the disease. "Therapeutically effective amount" means a dose of the compound of the present invention sufficient to achieve the goal.

[0171]

When the compound of the present invention is used as a medicine, the compound of the present invention can be used alone or as a pharmaceutical composition of the compound of the present invention in combination with a pharmaceutically acceptable carrier commonly used in the field of pharmaceuticals, according to a method known per se for the preparation of a pharmaceutical preparation. (for example, the method described in the Japanese Pharmacopoeia, etc.). The pharmaceutical composition is mixed with a carrier and an excipient, diluent, solubilizer, etc., which are commonly used in the pharmaceutical field, in the range that the desired effect of the present invention is not impaired, and it can be administered orally or parenterally in the form of a tablet, powder, granule , capsule, syrup, solution, injection, etc. The dosage form may be appropriately determined by those skilled in the art according to the intended use of the compound of the present invention. The dose varies depending on the symptoms, age, body weight of the patient, and the like. In general, 0.01-500 mg, preferably 0.05-300 mg, more preferably 0.1-150 mg, even more preferably 0.5-100 mg per day can be administered in one or more portions.

[Example]

[0172]

The compound of the present invention is specifically explained below; however, it is clear that the present invention is not limited to this.

[0173]

Example 1 (Compound 1)

3-[4-(4-bromothiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

(1-1) To a mixture of acetone/water (2:1) (120 ml) was added 3-bromopiperidine-2,6-dione (9.74 g, 50.73 mmol) and sodium azide (16.51 g, 253 .96 mmol) and the mixture was stirred under argon at room temperature for 24 hours. The acetone was evaporated and the remaining solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, treated with activated charcoal and concentrated. The concentrated residue was recrystallized from ethyl acetate to give 3-azidopiperidine-2,6-dione (6.26 g, 80%) as a gray solid.

¹ H-NMR(DMSO-d ₆ ) δ 11.06(1H, br s), 4.57(1H, dd, J=5.4, 11.9 Hz), 2.45-2.66( 2H, m), 1.99-2.10(1H, m), 1.78-1.93(1H, m).

[0174]

(1-2) To a solution of 3-bromo-4-ethynylthiophene (0.23 g, 1.23 mmol) in acetonitrile (6 ml) was added 3-azidopiperidine-2,6-dione (synthesized by the method according to example 1 (1- 1)) (0.19 g, 1.23 mmol) and copper(I) iodide (23.4 mg, 0.12 mmol) and the mixture was stirred under argon at room temperature for 48 h. the residue was purified by column chromatography (dichloromethane/methanol) to give 3-[4-(4-bromothiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione (0. 15 g, 36%) as a white solid.

¹ H-NMR(DMSO-d ₆ ) δ 11.17-11.31(1H, br), 8.66(1H, s), 8.05(1H, d, J=3.5 Hz), 7.87(1H, d, J=3.5Hz), 5.90(1H, dd, J=5.2, 12.6Hz), 2.65-2.96(3H, m), 2 .29-2.39(1H, m).

[0175]

Example 2 (Compound 2)

3-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

In a manner similar to that of Example 1 (1-2), 3-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione (99 mg, 58%) as a white solid from 3-ethynylthiophene (70 mg, 0.65 mmol).

¹ H-NMR(DMSO-d ₆ ) δ 11.27(1H, s), 8.54(1H, s), 7.87(1H, dd, J=1.2, 2.9 Hz), 7 .67(1H, dd, J=3.0, 5.0Hz), 7.52(1H, dd, J=1.2, 5.0Hz), 5.85(1H, dd, J=5 .2, 12.8 Hz), 2.84-2.95(1H, m), 2.61-2.75(2H, m), 2.32-2.41(1H, m).

[0176]

Example 3 (compound 3)

3-[4-(thiophen-2-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

To a solution of trimethyl(thiophen-2-ylethynyl)silane (560 mg, 3.11 mmol) in methanol (6 mL) was added potassium carbonate (858 mg, 6.21 mmol) and the mixture was stirred at room temperature for 1 h. water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give a colorless oil (350 mg). To a solution of the obtained colorless oil (350 mg) in acetonitrile (3 ml) was added 3-azidopiperidine-2,6-dione (synthesized by the method according to Example 1 (1-1)) (479 mg, 3.11 mmol) and copper iodide ( I) (59.1 mg, 0.31 mmol) and the mixture was stirred at room temperature for 20 h. The precipitate was collected by filtration and washed with methanol to give 3-[4-(thiophen-2-yl)-1H-1,2 ,3-triazol-1-yl]piperidin-2,6-dione (429 mg, 53%) as a gray solid.

¹ H-NMR(DMSO-d ₆ ) δ 11.28(1H, br s), 8.60(1H, s), 7.56(1H, dd, J=0.8, 5.0 Hz) , 7.44(1H, d, J=2.9 Hz), 7.15(1H, dd, J=3.6, 5.0 Hz), 5.86(1H, d, J=8.2 Hz), 2.80-2.98(1H, m), 2.60-2.80(2H, m), 2.30-2.45(1H, m).

[0177]

Example 4 (compound 4)

3-[5-chloro-4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

To a solution of 3-ethynylthiophene (0.80 ml, 8.04 mmol) in tetrahydrofuran (12 ml) was added dropwise a 1.64 M solution of n-butyllithium/hexane (5.60 ml, 9.18 mmol) at -78°C and the mixture was stirred at -78°C for 1 h. A suspension of N-chlorosuccinimide (2.37 g, 17.75 mmol) in tetrahydrofuran (30 ml) was added dropwise to the reaction mixture, and the mixture was stirred at -78° to room temperature over 19.5 hours. Hexane was added to the reaction mixture, and the mixture was washed with saturated brine and 1.0 M aqueous sodium thiosulfate, dried over anhydrous magnesium sulfate, and concentrated. The concentrated residue was purified by column chromatography (hexane/dichloromethane) to give a mixture of 3-(chloroethynyl)thiophene (723.3 mg) as a light yellow oil.

To a solution of the resulting mixture (723.3 mg) in acetonitrile (8 ml) was added 3-azidopiperidine-2,6-dione (624.7 mg, 4.05 mmol) and chlorine(pentamethylcyclopentadienyl)(cyclooctadiene)ruthenium (II) ( 78.7 mg, 0.21 mmol) and the mixture was stirred at 70° C. for 20 days. The reaction mixture was concentrated and the concentrated residue was purified by column chromatography (hexane/ethyl acetate) to give a crude product (137.6 mg). The resulting crude product was washed with ethyl acetate and chloroform to give 3-[5-chloro-4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione (44, 6 mg, 2%) as a gray solid.

¹ H-NMR(DMSO-d ₆ ) δ 11.34(1H, br s), 8.03(1H, dd, J=1.3, 2.9 Hz), 7.76(1H, dd, J=2.9, 5.0Hz), 7.64(1H, dd, J=1.3, 5.0Hz), 5.88(1H, dd, J=5.1, 12.5Hz ), 2.69-3.01(3H, m), 2.38-2.47(1H, m).

[0178]

Example 5 (compound 5)

3-[4-(5-methylthiophen-2-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

(5-1) Trimethylsilylacetylene (333 mg, 3.39 mmol), copper(I) iodide (53.8 mg, 0.28 mmol) and bis(triphenylphosphine)palladium (II) dichloride (99.1 mg, 0.14 mmol) and the mixture was stirred using a microwave reactor at 80°C for 1 h. The reaction mixture was purified by column chromatography with obtaining trimethyl[(5-methylthiophen-2-yl)ethynyl]silane (539 mg, 98%) as an orange oil.

¹ H-NMR(CDCl ₃ ) δ 7.23(1H, d, J=1.4 Hz), 6.76-6.78(1H, m), 2.43(3H, d, J=1, 0 Hz), 0.22(9H, s).

[0179]

(5-2) In a manner similar to that of Example 3, 3-[4-(5-methylthiophen-2-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione was obtained (291 mg, 38%) as a gray solid from trimethyl[(5-methylthiophen-2-yl)ethynyl]silane (539 mg, 2.77 mmol).

¹ H-NMR(DMSO-d ₆ ) δ 11.26(1H, s), 8.47(1H, s), 7.58(1H, d, J=1.3 Hz), 7.19-7 .23(1H, m), 5.83(1H, dd, J=5.0, 12.4 Hz), 2.89(1H, dd, J=4.0, 12.8, 17.6 Hz ), 2.58-2.77(2H, m), 2.49(3H, d, J=0.9 Hz), 2.29-2.41(1H, m).

[0180]

Example 6 (compound 6)

3-[4-(5-methylthiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

In a manner similar to that of Example 5, 3-[4-(5-methylthiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione was obtained as a blue solid (yield 16%) from 4-bromo-2-methylthiophene.

trimethyl[(5-methylthiophen-3-yl)ethynyl]silane

¹ H-NMR(CDCl ₃ ) δ 7.23(1H, d, J=1.3 Hz), 6.75-6.80(1H, m), 2.43(3H, d, J=1, 0 Hz), 0.23(9H, s).

3-[4-(5-methylthiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

¹ H-NMR(DMSO-d ₆ ) δ 11.26(1H, s), 8.47(1H, s), 7.58(1H, d, J=1.4 Hz), 7.21(1H , broad t, J=1.2 Hz), 5.83(1H, dd, J=5.1, 12.5 Hz), 2.84-2.94(1H, m), 2.60- 2.74(2H, m), 2.30-2.40(1H, m), 2.09(3H, s).

[0181]

Example 7 (compound 7)

3-[4-(4-methylthiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

(7-1) In a manner similar to that of Example 5 (5-1), trimethyl[(4-methylthiophen-3-yl)ethynyl]silane (293 mg, 54%) was obtained as a yellow oil from 3-bromo-4 -methylthiophene (500 mg, 2.82 mmol).

¹ H-NMR(CDCl ₃ ) δ 7.41 (1H, d, J=3.1 Hz), 6.84-6.89(1H, m), 2.27(3H, d, J=1, 0 Hz), 0.24(9H, s).

[0182]

(7-2) Potassium carbonate (601.6 mg, 4.35 mmol) was added to a solution of trimethyl[(4-methylthiophen-3-yl)ethynyl]silane (423 mg, 2.18 mmol) in methanol (6 ml) and the mixture was stirred at room temperature for 23 hours. The reaction mixture was filtered and the filtrate was concentrated. The concentrated residue was purified by column chromatography (hexane) to give a yellow oil (180 mg). In a manner similar to that of Example 1 (1-2), 3-[4-(4-methylthiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6 was obtained from the resulting oil -dione (117 mg, 19%) as a white, amorphous-like substance (180 mg).

¹ H-NMR(DMSO-d ₆ ) δ 11.26(1H, s), 8.47(1H, s), 7.80(1H, d, J=3.3 Hz), 7.27-7 .31(1H, m), 5.86(1H, dd, J=5.0, 12.5 Hz), 2.84-2.97(1H, m), 2.65-2.79(2H , m), 2.31-2.40(4H, m).

[0183]

Example 8 (compound 8)

3-[4-(5-acetylthiophen-2-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione

(8-1) Diisopropylamine (0.51 ml, 3.63 mmol), trimethylsilylacetylene (0.37 ml, 2.67 mmol), bis(triphenylphosphine)palladium(II) dichloride (86 mg, 0.12 mmol) and copper(I) iodide (12 mg, 0.06 mmol), and the mixture was sealed under argon and stirred at room temperature for 17 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give a mixture of 1-{5-[(trimethylsilyl)ethynyl]thiophen-2-yl}ethanone (0.64 g) as a brown solid. The resulting mixture was used for the next reaction without purification.

¹ H-NMR(CDCl ₃ ) δ 7.53(1H, d, J=4.0 Hz), 7.19(1H, d, J=4.0 Hz), 2.54(3H, s), 0.26(9H, s).

[0184]

(8-2) Potassium carbonate (0.80 g, 5.80 mmol) and the mixture was stirred under argon at room temperature for 1 h. The reaction mixture was filtered through celite and the filtrate was concentrated. Water was added to the concentrated residue and extracted with diethyl ether. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 1-(5-ethynylthiophen-2-yl)ethanone (0.19 g, 2 steps, 52%) as a brown solid.

¹ H-NMR(CDCl ₃ ) δ 7.54(1H, d, J=4.0 Hz), 7.25(1H, d, J=4.0 Hz), 3.51(1H, s), 2.55(3H, s).

[0185]

(8-3) In a manner similar to that of Example 1 (1-2), 3-[4-(5-acetylthiophen-2-yl)-1H-1,2,3-triazol-1-yl]piperidine- 2,6-dione (70.6 mg, 18%) as light brown solid from 1-(5-ethynylthiophen-2-yl)ethanone (0.19 g, 1.26 mmol).

¹ H-NMR(DMSO-d ₆ ) δ 11.31(1H, s), 8.81(1H, s), 7.96(1H, d, J=4.0 Hz), 7.56(1H , d, J=3.9 Hz), 5.90(1H, dd, J=5.2, 12.8 Hz), 2.83-2.96(1H, m), 2.58-2, 77(2H, m), 2.55(3H, s), 2.34-2.43(1H, m).

[0186]

Example 9 (compound 9)

3-{4-[5-(hydroxymethyl)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidin-2,6-dione

In a manner similar to that of Example 1 (1-2), 3-{4-[5-(hydroxymethyl)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidin-2,6 was obtained -dione (0.33 g, 29%) as a light purple solid from (4-ethynylthiophen-2-yl)methanol (0.53 g, 3.84 mmol).

¹ H-NMR(DMSO-d ₆ ) δ 11.26(1H, s), 8.50(1H, s), 7.72(1H, d, J=1.4 Hz), 7.32-7 .38(1H, m), 5.84(1H, dd, J=5.2, 12.6 Hz), 5.55(1H, t, J=5.8 Hz), 4.66(2H, dd, J=0.7, 5.8 Hz), 2.82-2.96(1H, m), 2.60-2.77(2H, m), 2.30-2.41(1H, m).

[0187]

Example 10 (compound 10)

3-[4-(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6- dion

In a manner similar to that of Example 1 (1-2), 3-[4-(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)-1H-1,2 was obtained, 3-triazol-1-yl]piperidin-2,6-dione (0.87 g, 33%) as a gray solid from 5-ethynyl-2,3-dihydrothieno[3,4-b][1,4 ]dioxin (1.36 g, 8.18 mmol).

¹ H-NMR(DMSO-d ₆ ) δ 11.23(1H, s), 8.33(1H, s), 6.62(1H, s), 5.87(1H, dd, J=5, 1, 12.4 Hz), 4.20-4.40(4H, m), 2.62-2.95(3H, m), 2.23-2.36(1H, m).

[0188]

Example 11 (compound 11)

3-[4-(5-chlorothiophen-2-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

(11-1) To a solution of 2-bromo-5-chlorothiophene (0.50 g, 2.53 mmol) in THF (5 ml) was added diisopropylamine (0.53 ml, 3.77 mmol), bis(triphenylphosphine) dichloride palladium(II) (88.9 mg, 0.13 mmol), copper(I) iodide (12.1 mg, 0.06 mmol) and trimethylsilylacetylene (0.37 ml, 2.67 mmol), and the mixture was sealed in argon atmosphere and stirred at 80° C. for 5 hours. A saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrated residue was purified by column chromatography (hexane) to give [(5-chlorothiophen-2-yl)ethynyl]trimethylsilane (0.51 g, 94%) as a light yellow oil.

¹ H-NMR(CDCl ₃ ) δ 6.99(1H, d, J=3.9 Hz), 6.76(1H, d, J=3.9 Hz), 0.24(9H, s).

[0189]

(11-2) In a manner similar to that of Example 8 (8-2, 8-3), 3-[4-(5-chlorothiophen-2-yl)-1H-1,2,3-triazol-1- yl]piperidin-2,6-dione as a gray solid (23% yield) from [(5-chlorothiophen-2-yl)ethynyl]trimethylsilane.

2-chloro-5-ethynylthiophene

¹ H-NMR(CDCl ₃ ) δ 7.05(1H, d, J=3.8 Hz), 6.79(1H, d, J=3.9 Hz), 3.32(1H, s).

3-[4-(5-chlorothiophen-2-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

¹ H-NMR(DMSO-d ₆ ) δ 11.28(1H, s), 8.64(1H, s), 7.32(1H, d, J=3.9 Hz), 7.17(1H , d, J=3.9 Hz), 5.87(1H, dd, J=5.1, 12.6 Hz), 2.82-2.95(1H, m), 2.60-2, 75(2H, m), 2.31-2.41(1H, m).

[0190]

Example 12 (compound 12)

3-[4-(5-bromothiophen-2-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

In a manner similar to that of Example 1 (1-2), 3-[4-(5-bromothiophen-2-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione was obtained (101.7 mg, 43%) as a gray solid from 2-bromo-5-ethynylthiophene (0.13 g, 0.69 mmol).

¹ H-NMR(DMSO-d ₆ ) δ 11.28(1H, s), 8.64(1H, s), 7.29(1H, d, J=3.9 Hz), 7.27(1H , d, J=3.8 Hz), 5.87(1H, dd, J=5.2, 12.6 Hz), 2.82-2.95(1H, m), 2.60-2, 76(2H, m), 2.31-2.42(1H, m).

[0191]

Example 13 (compound 13)

3-[4-(2,5-dibromothiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

(13-1) To a solution of 2,5-dibromothiophene-3-carboxyaldehyde (0.34 g, 1.26 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (0.32 g, 1.67 mmol) in methanol (13 ml) was added potassium carbonate (0.35 g, 2.53 mmol) and the mixture was stirred under argon at room temperature for 20 hours. The reaction mixture was concentrated and the concentrated residue was purified by column chromatography (hexane/ethyl acetate) with obtaining 2,5-dibromo-3-ethynylthiophene (0.30 g, 90%) as a light brown solid.

¹ H-NMR(CDCl ₃ ) δ 6.97(1H, s), 3.30(1H, s).

[0192]

(13-2) In a manner similar to that of Example 1 (1-2), 3-[4-(2,5-dibromothiophen-3-yl)-1H-1,2,3-triazol-1-yl] was obtained piperidine-2,6-dione (241.4 mg, 51%) as a light brown solid from 2,5-dibromo-3-ethynylthiophene (297.5 mg, 1.12 mmol).

¹ H-NMR(DMSO-d ₆ ) δ 11.28(1H, s), 8.79(1H, s), 7.64(1H, s), 5.92(1H, dd, J=5, 4, 12.8 Hz), 2.83-2.96(1H, m), 2.64-2.83(2H, m), 2.30-2.40(1H, m).

[0193]

Example 14 (compound 14)

3-[4-(4-chlorothiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

In a manner similar to that of Example 1 (1-2), 3-[4-(4-chlorothiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione was obtained (67.8 mg, 51%) as a white solid from 3-chloro-4-ethynylthiophene (64.1 mg, 0.45 mmol).

¹ H-NMR(DMSO-d ₆ ) δ 11.26(1H, s)8.65(1H, s), 8.10(1H, d, J=3.6 Hz), 7.77(1H, d, J=3.6 Hz), 5.90(1H, dd, J=5.1, 12.5 Hz), 2.65-2.95(3H, m), 2.30-2.40 (1H, m).

[0194]

Example 15 (compound 15)

3-[4-(4-Methoxy-5-methylthiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

(15-1) In an argon atmosphere, to a suspension of lithium aluminum hydride (0.36 g, 9.49 mmol) in diethyl ether (80 ml) was added dropwise a solution of methyl 4-bromo-3-methoxythiophene-2-carboxylate (2.01 g , 8.00 mmol) in diethyl ether (14 ml) at not more than 5°C, and the mixture was stirred at 0°C for 2 hours. Water was added to the reaction mixture, and the mixture was filtered through celite. Water was added to the filtrate, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrated residue was purified by column chromatography (dichloromethane/methanol) to give (4-bromo-3-methoxythiophen-2-yl)methanol (1.29 g, 72%) as a brown oil.

¹ H-NMR(CDCl ₃ ) δ 7.15(1H, s), 4.77(2H, d, J=5.8 Hz), 3.90(3H, s), 1.92(1H, t , J=5.9 Hz).

[0195]

(15-2) To a solution of (4-bromo-3-methoxythiophen-2-yl)methanol (1.29 g, 5.78 mmol) in dichloromethane (12 ml) was added thionyl chloride (0.50 ml, 6.89 mmol ) at 0°C and the mixture was stirred under argon at room temperature for 4.5 hours. After 2 hours and 3 hours, thionyl chloride (0.25 ml, 3.45 mmol) was added at 0°C. Water was added to the reaction mixture at 0°C, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, treated with activated charcoal and concentrated to give 4-bromo-2-(chloromethyl)-3-methoxythiophene (1.32 g, 95%) as a yellow oil. The resulting 4-bromo-2-(chloromethyl)-3-methoxythiophene was used for the next reaction without purification.

¹ H-NMR(CDCl ₃ ) δ 7.20(1H, s), 4.74(2H, s), 3.94(3H, s).

[0196]

(15-3) In an argon atmosphere, a solution of 4-bromo-2-(chloromethyl)-3-methoxythiophene (1.32 g , 5.47 mmol) in tetrahydrofuran (10 ml) at not more than 5°C, and the mixture was stirred at 0°C for 5 hours. Water was added to the reaction mixture, and the mixture was filtered through celite. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrated residue was purified by column chromatography (hexane/dichloromethane) to give 4-bromo-3-methoxy-2-methylthiophene (0.72 g, 64%) as a colorless oil.

¹ H-NMR(CDCl ₃ ) δ 6.95(1H, s), 3.81(3H, s), 2.37(3H, s).

[0197]

(15-4) In a manner similar to that of Example 11, 3-[4-(4-methoxy-5-methylthiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2 was obtained ,6-dione as a gray solid (34% yield) from 4-bromo-3-methoxy-2-methylthiophene.

[(4-methoxy-5-methylthiophen-3-yl)ethynyl]trimethylsilane

¹ H-NMR(CDCl ₃ ) δ 7.13(1H, s), 3.90(3H, s), 2.28(3H, s), 0.24(9H, s).

4-ethynyl-3-methoxy-2-methylthiophene

¹ H-NMR(CDCl ₃ ) δ 7.18(1H, s), 3.90(3H, s), 3.16(1H, s), 2.31(3H, s).

3-[4-(4-Methoxy-5-methylthiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

¹ H-NMR(DMSO-d ₆ ) δ 11.23(1H, br s), 8.35(1H, s), 7.60(1H, s), 5.86(1H, dd, J= 5.1, 12.4 Hz), 3.73(3H, s), 2.63-2.96(3H, m), 2.25-2.41(4H, m).

[0198]

Example 16 (compound 16)

methyl 4-[1-(2,6-dioxopiperidin-3-yl)-1H-1,2,3-triazol-4-yl]-3-methoxythiophene-2-carboxylate

In a manner similar to that of Example 11, methyl 4-[1-(2,6-dioxopiperidin-3-yl)-1H-1,2,3-triazol-4-yl]-3-methoxythiophene-2-carboxylate was obtained in as a gray solid (36% yield) from methyl 4-bromo-3-methoxythiophene-2-carboxylate.

methyl 3-methoxy-4-[(trimethylsilyl)ethynyl]thiophene-2-carboxylate

¹ H-NMR(CDCl ₃ ) δ 7.50(1H, s), 4.13(3H, s), 3.86(3H, s), 0.24(9H, s).

methyl 4-ethynyl-3-methoxythiophene-2-carboxylate

¹ H-NMR(CDCl ₃ ) δ 7.56(1H, s), 4.13(3H, s), 3.87(3H, s), 3.21(1H, s).

methyl 4-[1-(2,6-dioxopiperidin-3-yl)-1H-1,2,3-triazol-4-yl]-3-methoxythiophene-2-carboxylate

¹ H-NMR(DMSO-d ₆ ) δ 11.26(1H, s), 8.48(1H, s), 8.23(1H, s), 5.89(1H, dd, J=5, 0, 12.4 Hz), 3.98(3H, s), 3.83(3H, s), 2.64-2.97(3H, m), 2.27-2.38(1H, m ).

[0199]

Example 17 (compound 17)

3-[4-(4-ethoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

In a manner similar to that of Example 11, 3-[4-(4-ethoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione was obtained as a light brown solid (30% yield) from 3-bromo-4-ethoxythiophene.

[(4-ethoxythiophen-3-yl)ethynyl]trimethylsilane

¹ H-NMR(CDCl ₃ ) δ 7.36(1H, d, J=3.3 Hz), 6.15(1H, d, J=3.3 Hz), 4.04(2H, q, J =7.0 Hz), 1.45(3H, t, J=7.0 Hz), 0.25(9H, s).

3-ethoxy-4-ethynylthiophene

¹ H-NMR(CDCl ₃ ) δ 7.41(1H, d, J=3.3 Hz), 6.18(1H, d, J=3.3 Hz), 4.07(2H, q, J =7.0 Hz), 3.17(1H, s), 1.46(3H, t, J=7.0 Hz).

3-[4-(4-ethoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

¹ H-NMR(DMSO-d ₆ ) δ 11.23(1H, s), 8.27(1H, s), 7.88(1H, d, J=3.4 Hz), 6.73(1H , d, J=3.4 Hz), 5.88(1H, dd, J=5.0, 12.3 Hz), 4.11(2H, q, J=7.0 Hz), 2.64 -2.92(3H, m), 2.26-2.36(1H, m), 1.42(3H, t, J=7.0 Hz).

[0200]

Example 18 (compound 18)

3-[4-(2-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

In a manner similar to that of Example 13, 3-[4-(2-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione was obtained as a gray solid (25% yield) from 2-methoxythiophene-3-carboxyaldehyde.

3-ethynyl-2-methoxythiophene

¹ H-NMR(CDCl ₃ ) δ 6.82(1H, d, J=5.8 Hz), 6.50(1H, d, J=5.8 Hz), 4.02(3H, s), 3.21(1H, s).

3-[4-(2-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

¹ H-NMR(DMSO-d ₆ ) δ 11.23(1H, s), 8.33(1H, s), 7.35(1H, d, J=5.8 Hz), 6.94(1H , d, J=5.8 Hz), 5.85(1H, dd, J=5.1, 12.5 Hz), 4.00(3H, s), 2.63-2.94(3H, m), 2.25-2.35(1H, m).

[0201]

Example 19 (compound 19)

3-[4-(4-Methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

In a manner similar to that of Example 13, 3-[4-(4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione was obtained as a gray solid (yield 64%) from 4-methoxythiophene-3-carboxyaldehyde.

3-ethynyl-4-methoxythiophene

¹ H-NMR(CDCl ₃ ) δ 7.42(1H, d, J=3.3 Hz), 6.21(1H, d, J=3.3 Hz), 3.88(3H, s), 3.19(1H, s).

3-[4-(4-Methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

¹ H-NMR(DMSO-d ₆ ) δ 11.23(1H, s), 8.35(1H, s), 7.88(1H, d, J=3.4 Hz), 6.75(1H , d, J=3.4 Hz), 5.86(1H, dd, J=5.1, 12.5 Hz), 3.88(3H, s), 2.63-2.94(3H, m), 2.27-2.35(1H, m).

[0202]

Example 20 (compound 20)

3-[4-(5-Methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

In a manner similar to that of Example 1 (1-2), 3-[4-(5-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione was obtained (0.80 g, 59%) as a light brown solid from 4-ethynyl-2-methoxythiophene (0.64 g, 4.63 mmol).

¹ H-NMR(DMSO-d ₆ ) δ 11.26(1H, s), 8.47(1H, s), 7.07(1H, d, J=1.7 Hz), 6.71(1H , d, J=1.7 Hz), 5.83(1H, dd, J=5.2, 12.7 Hz), 3.91(3H, s), 2.82-2.95(1H, m), 2.59-2.75(2H, m), 2.30-2.40(1H, m).

[0203]

Example 21 (compound 21)

3-[4-(4-propoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

In a manner similar to that of Example 13, 3-[4-(4-propoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione was obtained as light brown solid (50% yield) from 4-propoxythiophene-3-carboxyaldehyde.

3-ethynyl-4-propoxythiophene

¹ H-NMR(CDCl ₃ ) δ 7.40(1H, d, J=3.3 Hz), 6.17(1H, d, J=3.3 Hz), 3.95(2H, t, J =6.6 Hz), 3.16(1H, s), 1.80-1.91(2H, m), 1.04(3H, t, J=7.4 Hz).

3-[4-(4-propoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

¹ H-NMR(DMSO-d ₆ ) δ 11.23(1H, s), 8.22(1H, s), 7.88(1H, d, J=3.3 Hz), 6.73(1H , d, J=3.4 Hz), 5.88(1H, dd, J=5.0, 12.4 Hz), 3.97-4.06(2H, m), 2.65-2, 93(3H, m), 2.28-2.38(1H, m), 1.77-1.89(2H, m), 1.01(3H, t, J=7.4 Hz).

[0204]

Example 22 (compound 22)

3-[4-(5-Chloro-4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

(22-1) To a solution of 4-methoxythiophene-3-carboxyaldehyde (200 mg, 1.41 mmol) in chloroform (1.4 ml) was added 2-chloro-1,3-bis(methoxycarbonyl)guanidine (354.3 mg , 1.69 mmol) and the mixture was stirred under argon atmosphere at room temperature for 30 hours. The reaction mixture was concentrated and the concentrated residue was purified by column chromatography (hexane/ethyl acetate) to give 5-chloro-4-methoxythiophene-3-carboxyaldehyde (151 mg, 60%) as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ 9.80(1H, s), 7.83(1H, s), 4.03(3H, s).

[0205]

(22-2) In a manner similar to that of Example 13, 3-[4-(5-chloro-4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2 was obtained ,6-dione as a white solid (49% yield) from 5-chloro-4-methoxythiophene-3-carboxyaldehyde.

2-chloro-4-ethynyl-3-methoxythiophene

¹ H-NMR(CDCl ₃ ) δ 7.21(1H, s), 4.01(3H, s), 3.19(1H, s).

3-[4-(5-Chloro-4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

¹ H-NMR(DMSO-d ₆ ) δ 11.25(1H, s), 8.44(1H, s), 7.81(1H, s), 5.88(1H, dd, J=5, 1, 12.5 Hz), 3.90(3H, s), 2.65-2.95(3H, m), 2.27-2.37(1H, m).

[0206]

Example 23 (compound 23)

3-[4-(5-bromo-4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

(23-1) N-bromosuccinimide (131.6 mg, 0.74 mmol) was added in small portions at 0 °C and the mixture was stirred at 0°C for 1 h. The reaction mixture was concentrated and the concentrated residue was purified by column chromatography (hexane/ethyl acetate) to give 5-bromo-4-methoxythiophene-3-carboxyaldehyde (0.16 g) as a light brown oil. The resulting 5-bromo-4-methoxythiophene-3-carboxyaldehyde was used for the next reaction without purification.

¹ H-NMR(CDCl ₃ ) δ 9.81(1H, s), 8.00(1H, s), 4.01(3H, s).

[0207]

(23-2) In a manner similar to that of Example 13, 3-[4-(5-bromo-4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2 was obtained ,6-dione as a white solid (46% yield) from 5-bromo-4-methoxythiophene-3-carboxyaldehyde.

2-bromo-4-ethynyl-3-methoxythiophene

¹ H-NMR(CDCl ₃ ) δ 7.39(1H, s), 4.00(3H, s), 3.20(1H, s).

3-[4-(5-bromo-4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

¹ H-NMR(DMSO-d ₆ ) δ 11.24(1H, s), 8.44(1H, s), 7.96(1H, s), 5.88(1H, dd, J=5, 1, 12.5 Hz), 3.86(3H, s), 2.65-2.96(3H, m), 2.27-2.38(1H, m).

[0208]

Example 24 (compound 24)

3-[4-(5-ethoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

(24-1) To a solution of 5-bromothiophene-3-carboxyaldehyde (9.96 g, 52.13 mmol) in methanol (78 ml) was added methyl orthoformate (8.56 ml, 78.24 mmol) and ammonium chloride (0. 39 g, 7.29 mmol) and the mixture was stirred under argon atmosphere at 60° C. for 3.5 hours. The reaction mixture was concentrated, diethyl ether was added to the concentrated residue and the mixture was filtered. The filtrate was concentrated and the concentrated residue was purified by column chromatography (hexane/ethyl acetate) to give 2-bromo-4-(dimethoxymethyl)thiophene (11.80 g, 95%) as a yellow oil.

¹ H-NMR(CDCl ₃ ) δ 7.23(1H, dd, J=1.0, 1.5 Hz), 7.05(1H, d, J=1.5 Hz), 5.37(1H , d, J=0.7 Hz), 3.31(6H, s).

[0209]

(24-2) Ethanol (2.53 ml) was slowly added to a suspension of sodium hydride (60%) (0.38 g, 9.50 mmol) in N,N-dimethylformamide (1.27 ml) and the mixture was stirred at room temperature. temperature until foaming stops. To this solution were added 2-bromo-4-(dimethoxymethyl)thiophene (0.50 g, 2.11 mmol) and copper(I) bromide (15.1 mg, 0.11 mmol) and the mixture was reacted under argon with using a microwave reactor at 160°C for 15 min. The reaction mixture was filtered through celite and the filtrate was concentrated. The concentrated residue was purified by column chromatography (hexane/ethyl acetate) to give 4-(dimethoxymethyl)-2-ethoxythiophene (0.19 g, 48%) as a yellow oil.

¹ H-NMR(CDCl ₃ ) δ 6.56(1H, dd, J=1.0, 1.6 Hz), 6.19(1H, d, J=1.6 Hz), 5.28(1H , d, J=0.7 Hz), 4.08(2H, q, J=7.0 Hz), 3.32(6H, s), 1.40(3H, t, J=7.0 Hz ).

[0210]

(24-3) To a solution of 4-(dimethoxymethyl)-2-ethoxythiophene (0.58 g, 3.11 mmol) in methanol (10 ml) was added 4.0 M hydrochloric acid (10 ml) and the mixture was stirred at room temperature within 20 min. Saturated brine was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrated residue was purified by column chromatography (hexane/ethyl acetate) to give 5-ethoxythiophene-3-carboxyaldehyde (0.32 g, 66%) as a yellow oil.

¹ H-NMR(CDCl ₃ ) δ 9.67(1H, s), 7.39(1H, d, J=1.6 Hz), 6.57(1H, d, J=1.6 Hz), 4.13(2H, q, J=7.0 Hz), 1.43(3H, t, J=7.0 Hz).

[0211]

(24-4) In a manner similar to that of Example 13, 3-[4-(5-ethoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione was obtained as a light brown solid (46% yield) from 5-ethoxythiophene-3-carboxyaldehyde.

2-ethoxy-4-ethynylthiophene

¹ H-NMR(CDCl ₃ ) δ 6.77(1H, d, J=1.6 Hz), 6.22(1H, d, J=1.6 Hz), 4.08(2H, q, J =7.0 Hz), 2.96(1H, s), 1.41(3H, t, J=7.0 Hz).

3-[4-(5-ethoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

¹ H-NMR(DMSO-d ₆ ) δ 11.26(1H, s), 8.46(1H, s), 7.07(1H, d, J=1.6 Hz), 6.70(1H , d, J=1.6 Hz), 5.83(1H, dd, J=5.0, 12.7 Hz), 4.15(2H, q, J=7.0 Hz), 2.89 (1H, ddd, J=5.0, 13.1, 18.1 Hz), 2.58-2.75(2H, m), 2.30-2.40(1H, m), 1.36 (3H, t, J=7.0 Hz).

[0212]

Example 25 (compound 25)

3-[4-(4-butoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

(25-1) Copper(I) bromide (0 .36 g, 2.51 mmol) and sodium 1-butoxide (22.4 w/w% in 1-BuOH) (3.74 g, 8.72 mmol) and the mixture was reacted under argon using a microwave reactor at 160°C for 15 min. The same reaction was run for 2 batches and the reaction mixtures from both batches were combined and filtered through celite. Saturated brine was added to the filtrate, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrated residue was purified by column chromatography (hexane/ethyl acetate) to give 3-butoxy-4-(diethoxymethyl)thiophene (0.95 g, 74%) as a light yellow oil.

¹ H-NMR(CDCl ₃ ) δ 7.32(1H, dd, J=0.6, 3.4 Hz), 6.17(1H, d, J=3.4 Hz), 5.48(1H , d, J=0.6 Hz), 3.96(2H, t, J=6.4 Hz), 3.51-3.69(4H, m), 1.71-1.81(2H, m), 1.42-1.54(2H, m), 1.22(6H, t, J=7.1 Hz), 0.96(3H, t, J=7.4 Hz).

[0213]

(25-2) In a manner similar to that of Example 24(24-3, 24-4), 3-[4-(4-butoxythiophen-3-yl)-1H-1,2,3-triazole-1- yl]piperidine-2,6-dione as light brown solid (54% yield) from 3-butoxy-4-(diethoxymethyl)thiophene.

4-butoxythiophene-3-carboxyaldehyde

¹ H-NMR(CDCl ₃ ) δ 9.91(1H, s), 8.01(1H, d, J=3.4 Hz), 6.27(1H, d, J=3.4 Hz), 4.03(2H, t, J=6.4Hz), 1.77-1.87(2H, m), 1.45-1.57(2H, m), 0.99(3H, t, J=7.4 Hz).

3-butoxy-4-ethynylthiophene

¹ H-NMR(CDCl ₃ ) δ 7.40(1H, d, J=3.4 Hz), 6.17(1H, d, J=3.3 Hz), 3.99(2H, t, J =6.6 Hz), 3.15(1H, s), 1.76-1.86(2H, m), 1.44-1.57(2H, m), 0.98(3H, t, J=7.4 Hz).

3-[4-(4-butoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

¹ H-NMR(DMSO-d ₆ ) δ 11.23(1H, s), 8.21(1H, s), 7.88(1H, d, J=3.4 Hz), 6.73(1H , d, J=3.4 Hz), 5.88(1H, dd, J=5.3, 12.6 Hz), 4.01-4.11(2H, m), 2.64-2, 93(3H, m), 2.27-2.38(1H, m), 1.75-1.85(2H, m), 1.40-1.51(2H, m), 0.95( 3H, t, J=7.4 Hz).

[0214]

Example 26 (compound 26)

3-[4-(4-isopropoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione

(26-1) To a suspension of sodium hydride (60%) (0.38 g, 9.50 mmol) in N,N-dimethylformamide (1.27 ml) was slowly added 2-propanol (2.53 ml) and the mixture was stirred at room temperature until foaming stops. To this solution were added 3-bromo-4-(dimethoxymethyl)thiophene (0.50 g, 2.11 mmol) and copper(I) bromide (0.30 g, 2.09 mmol) and the mixture was reacted under argon with using a microwave reactor at 160°C for 15 min. Diethyl ether (2 ml) was added to the reaction mixture, and the mixture was filtered through celite. The same reaction was carried out for 2 batches and the filtrates from both batches were pooled. Saturated brine was added to the solution, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, treated with activated charcoal and concentrated to give a tan oil (1.49 g). To a solution of the resulting tan oil (1.49 g) in methanol (10 ml) was added 4.0 M hydrochloric acid (10 ml) and the mixture was stirred under argon at room temperature for 20 minutes. Saturated brine was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrated residue was purified by column chromatography (hexane/ethyl acetate) to give a mixture of 4-isopropoxythiophene-3-carboxyaldehyde (0.65 g) as a yellow oil. The resulting 4-isopropoxythiophene-3-carboxyaldehyde mixture was used for the next reaction without purification.

¹ H-NMR(CDCl ₃ ) δ 9.88(1H, s), 8.00(1H, d, J=3.3 Hz), 6.26(1H, d, J=3.3 Hz), 4.47(1H, sep, J=6.1Hz), 1.40(6H, d, J=6.1Hz).

[0215]

(26-2) In a manner similar to that of Example 13, 3-[4-(4-isopropoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione was obtained as a gray solid from a mixture of 4-isopropoxythiophene-3-carboxyaldehyde (from 3-bromo-4-(dimethoxymethyl)thiophene, 4 steps, 16%).

3-ethynyl-4-isopropoxythiophene

¹ H-NMR(CDCl ₃ ) δ 7.39(1H, d, J=3.3 Hz), 6.20(1H, d, J=3.3 Hz), 4.42(1H, sept, J =6.1 Hz), 3.15(1H, s), 1.38(6H, d, J=6.1 Hz).

3-[4-(4-isopropoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione

¹ H-NMR(DMSO-d ₆ ) δ 11.23(1H, s), 8.24(1H, s), 7.86(1H, d, J=3.3 Hz), 6.74(1H , d, J=3.3 Hz), 5.87(1H, dd, J=4.9, 12.2 Hz), 4.56(1H, sep, J=6.0 Hz), 2.65 -2.93(3H, m), 2.28-2.36(1H, m), 1.36(6H, d, J=6.0 Hz).

[0216]

Example 27 (compound 27)

3-{4-[4-(cyclopentyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione

(27-1) To a solution of methyl 4-bromo-3-hydroxythiophene-2-carboxylate (1.00 g, 4.22 mmol) in N,N-dimethylformamide (14 ml) was added cyclopentyl bromide (1.13 ml, 10. 54 mmol) and cesium carbonate (3.44 g, 10.56 mmol) and the mixture was stirred under argon atmosphere at 100-110° C. for 48 hours. Water was added to the reaction mixture and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrated residue was purified by column chromatography (hexane/ethyl acetate) to give methyl 4-bromo-3-(cyclopentyloxy)thiophene-2-carboxylate (1.20 g, 93%) as a colorless oil.

¹ H-NMR(CDCl ₃ ) δ 7.38(1H, s), 5.10-5.17(1H, m), 3.87(3H, s), 1.85-2.04(4H, m), 1.69-1.82(2H, m), 1.55-1.69(2H, m).

[0217]

(27-2) To a solution of methyl 4-bromo-3-(cyclopentyloxy)thiophene-2-carboxylate (1.20 g, 3.93 mmol) in methanol (6.7 ml) was added water (2.8 ml) and potassium hydroxide (85%) (0.31 g, 4.70 mmol) and the mixture was refluxed for 3 hours. The reaction mixture was concentrated, water was added to the concentrated residue and the mixture was washed with diethyl ether. 2.0 M hydrochloric acid (2.5 ml) was added to the aqueous layer, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 4-bromo-3-(cyclopentyloxy)thiophene-2-carboxylic acid (1.05 g, 92%) as a white solid. The resulting 4-bromo-3-(cyclopentyloxy)thiophene-2-carboxylic acid was used for the next reaction without purification.

¹ H-NMR(CDCl ₃ ) δ 7.51(1H, s), 5.30-5.36(1H, m), 1.78-2.05(6H, m), 1.63-1, 73(2H, m).

[0218]

(27-3) To a solution of 4-bromo-3-(cyclopentyloxy)thiophene-2-carboxylic acid (1.05 g, 3.61 mmol) in quinoline (15 ml) was added powdered copper (0.26 g, 4 09 mmol) and the mixture was stirred under argon atmosphere at 150°C for 15 min. 2.0 M hydrochloric acid (65 ml) was added to the reaction mixture, and the mixture was filtered through celite, and the filtrate was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrated residue was purified by column chromatography (hexane/ethyl acetate) to give 3-bromo-4-(cyclopentyloxy)thiophene (0.81 g, 91%) as a colorless oil.

¹ H-NMR(CDCl ₃ ) δ 7.16(1H, d, J=3.5 Hz), 6.18(1H, d, J=3.5 Hz), 4.64-4.70(1H , m), 1.76-1.98(6H, m), 1.56-1.68(2H, m).

[0219]

(27-4) In a manner similar to that of Example 11, 3-{4-[4-(cyclopentyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidin-2, 6-dione as a blue solid (8% yield) from 3-bromo-4-(cyclopentyloxy)thiophene.

{[4-(cyclopentyloxy)thiophen-3-yl]ethynyl}trimethylsilane

¹ H-NMR(CDCl ₃ ) δ 7.33(1H, d, J=3.3 Hz), 6.14(1H, d, J=3.3 Hz), 4.67(1H, sep, J =2.7 Hz), 1.76-2.06(6H, m), 1.56-1.70(2H, m), 0.24(9H, s).

3-(cyclopentyloxy)-4-ethynylthiophene

¹ H-NMR(CDCl ₃ ) δ 7.38(1H, d, J=3.3 Hz), 6.14(1H, d, J=3.4 Hz), 4.63-4.70(1H , m), 3.12(1H, s), 1.75-1.98(6H, m), 1.54-1.69(2H, m).

3-{4-[4-(cyclopentyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione

¹ H-NMR(DMSO-d ₆ ) δ 11.22(1H, s), 8.17(1H, s), 7.87(1H, d, J=3.3 Hz), 6.68(1H , d, J=3.3 Hz), 5.88(1H, dd, J=5.2, 12.5 Hz), 4.76-4.84(1H, m), 2.65-2, 92(3H, m), 2.27-2.37(1H, m), 1.91-2.02(2H, m), 1.80-1.91(2H, m), 1.67- 1.80(2H, m), 1.53-1.67(2H, m).

[0220]

Example 28 (compound 28)

3-{4-[4-(cyclopropylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione

In a manner similar to that of Example 27, 3-{4-[4-(cyclopropylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione was obtained as gray solid (yield 14%) from methyl 4-bromo-3-hydroxythiophene-2-carboxylate and (bromomethyl)cyclopropane.

methyl 4-bromo-3-(cyclopropylmethoxy)thiophene-2-carboxylate

¹ H-NMR(CDCl ₃ ) δ 7.38(1H, s), 4.02(2H, d, J=7.2 Hz), 3.87(3H, s), 1.29-1.41 (1H, m), 0.58-0.65(2H, m), 0.31-0.38(2H, m).

4-bromo-3-(cyclopropylmethoxy)thiophene-2-carboxylic acid

¹ H-NMR(CDCl ₃ ) δ 7.51(1H, s), 4.16(2H, d, J=7.4 Hz), 1.27-1.39(1H, m), 0.64 -0.71(2H, m), 0.33-0.40(2H, m).

3-bromo-4-(cyclopropylmethoxy)thiophene

¹ H-NMR(CDCl ₃ ) δ 7.18(1H, d, J=3.5 Hz), 6.21(1H, d, J=3.5 Hz), 3.83(2H, d, J =6.8 Hz), 1.25-1.38(1H, m), 0.61-0.69(2H, m), 0.34-0.41(2H, m).

{[4-(cyclopropylmethoxy)thiophen-3-yl]ethynyl}trimethylsilane

¹ H-NMR(CDCl ₃ ) δ 7.35(1H, d, J=3.3 Hz), 6.15(1H, d, J=3.4 Hz), 3.84(2H, d, J = 6.7 Hz), 1.23-1.37(1H, m), 0.56-0.73(2H, m), 0.35-0.42(2H, m), 0.25( 9H, c).

3-(cyclopropylmethoxy)-4-ethynylthiophene

¹ H-NMR(CDCl ₃ ) δ 7.41(1H, d, J=3.4 Hz), 6.17(1H, d, J=3.4 Hz), 3.83(2H, d, J =6.9 Hz), 3.18(1H, s), 1.20-1.47(1H, m), 0.56-0.74(2H, m), 0.34-0.41( 2H, m).

3-{4-[4-(cyclopropylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione

¹ H-NMR(DMSO-d ₆ ) δ 11.23(1H, s), 8.24(1H, s), 7.87(1H, d, J=3.3 Hz), 6.72(1H , d, J=3.4 Hz), 5.89(1H, dd, J=5.3, 12.6 Hz), 3.87-3.97(2H, m), 2.65-2, 94(3H, m), 2.30-2.40(1H, m), 1.28-1.40(1H, m), 0.59(2H, ddd, J=4.2, 6.0 , 8.0 Hz), 0.34-0.41(2H, m).

[0221]

Example 29 (compound 29)

3-{4-[4-(cyclopentylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione

In a manner similar to that of Example 27, 3-{4-[4-(cyclopentylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione was obtained as white solid (yield 17%) from methyl 4-bromo-3-hydroxythiophene-2-carboxylate and (iodomethyl)cyclopentane.

methyl 4-bromo-3-(cyclopentylmethoxy)thiophene-2-carboxylate

¹ H-NMR(CDCl ₃ ) δ 7.38(1H, s), 4.05(2H, d, J=6.9 Hz), 3.87(3H, s), 2.43(1H, sep , J=7.4 Hz), 1.80-1.91(2H, m), 1.53-1.71(4H, m), 1.41-1.51(2H, m).

4-bromo-3-(cyclopentylmethoxy)thiophene-2-carboxylic acid

¹ H-NMR(CDCl ₃ ) δ 7.49(1H, s), 4.14(2H, d, J=7.0 Hz), 2.44(1H, sep, J=7.5 Hz), 1.79-1.94(2H, m), 1.53-1.73(4H, m), 1.36-1.51(2H, m).

3-bromo-4-(cyclopentylmethoxy)thiophene

¹ H-NMR(CDCl ₃ ) δ 7.17(1H, d, J=3.5 Hz), 6.20(1H, d, J=3.5 Hz), 3.86(2H, d, J =6.8 Hz), 2.41(1H, sep, J=7.5 Hz), 1.78-1.90(2H, m), 1.53-1.72(4H, m), 1 .33-1.44(2H, m).

{[4-(cyclopentylmethoxy)thiophen-3-yl]ethynyl}trimethylsilane

¹ H-NMR(CDCl ₃ ) δ 7.34(1H, d, J=3.3 Hz), 6.14(1H, d, J=3.3 Hz), 3.85(2H, d, J =6.6Hz), 2.40(1H, sep, J=7.3Hz), 1.77-1.88(2H, m), 1.52-1.73(4H, m), 1 .37-1.48(2H, m), 0.24(9H, s).

3-(cyclopentylmethoxy)-4-ethynylthiophene

¹ H-NMR(CDCl ₃ ) δ 7.39(1H, d, J=3.4 Hz), 6.17(1H, d, J=3.4 Hz), 3.85(2H, d, J =6.9Hz), 3.14(1H, s), 2.42(1H, sep, J=7.4Hz), 1.79-1.89(2H, m), 1.52-1 .71(4H, m), 1.32-1.43(2H, m).

3-{4-[4-(cyclopentylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione

¹ H-NMR(DMSO-d ₆ ) δ 11.23(1H, s), 8.16(1H, s), 7.88(1H, d, J=3.4 Hz), 6.73(1H , d, J=3.4 Hz), 5.89(1H, dd, J=5.2, 12.6 Hz), 3.89-3.99(2H, m), 2.65-2, 93(3H, m), 2.29-2.48(2H, m), 1.78-1.90(2H, m), 1.49-1.69(4H, m), 1.27- 1.40(2H, m).

[0222]

Example 30 (compound 30)

3-{4-[4-(cyclohexylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione

In a manner similar to that of Example 27, 3-{4-[4-(cyclohexylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione was obtained as red-brown solid (yield 15%) from methyl 4-bromo-3-hydroxythiophene-2-carboxylate and (bromomethyl)cyclohexane.

methyl 4-bromo-3-(cyclohexylmethoxy)thiophene-2-carboxylate

¹ H-NMR(CDCl ₃ ) δ 7.37(1H, s), 3.96(2H, d, J=6.2 Hz), 3.87(3H, s), 1.65-1.98 (6H, m), 1.06-1.38(5H, m).

4-bromo-3-(cyclohexylmethoxy)thiophene-2-carboxylic acid

¹ H-NMR(CDCl ₃ ) δ 7.49(1H, s), 4.05(2H, d, J=6.0 Hz), 1.66-1.97(6H, m), 1.06 -1.39(5H, m).

3-bromo-4-(cyclohexylmethoxy)thiophene

¹ H-NMR(CDCl ₃ ) δ 7.17(1H, d, J=3.5 Hz), 6.19(1H, d, J=3.4 Hz), 3.77(2H, d, J =6.1 Hz), 1.65-1.93(6H, m), 1.14-1.38(3H, m), 0.99-1.14(2H, m).

{[4-(cyclohexylmethoxy)thiophen-3-yl]ethynyl}trimethylsilane

¹ H-NMR(CDCl ₃ ) δ 7.33(1H, d, J=3.3 Hz), 6.13(1H, d, J=3.3 Hz), 3.76(2H, d, J =6.0 Hz), 1.65-1.92(6H, m), 1.03-1.37(5H, m), 0.24(9H, s).

3-(cyclohexylmethoxy)-4-ethynylthiophene

¹ H-NMR(CDCl ₃ ) δ 7.39(1H, d, J=3.4 Hz), 6.15(1H, d, J=3.3 Hz), 3.77(2H, d, J =6.1 Hz), 3.14(1H, s), 1.80-1.93(3H, m), 1.65-1.80(3H, m), 1.13-1.36( 3H, m), 0.99-1.13(2H, m).

3-{4-[4-(cyclohexylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione

¹ H-NMR(DMSO-d ₆ ) δ 11.23(1H, s), 8.17(1H, s), 7.87(1H, d, J=3.4 Hz), 6.72(1H , d, J=3.4 Hz), 5.88(1H, dd, J=5.1, 12.4 Hz), 3.83-3.93(2H, m), 2.65-2, 93(3H, m), 2.31-2.40(1H, m), 1.61-1.92(6H, m), 1.01-1.35(5H, m).

[0223]

Example 31 (compound 31)

3-{4-[4-(4-methoxybenzyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione

In a manner similar to that of Example 27, 3-{4-[4-(4-methoxybenzyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidin-2,6-dione was obtained as a white solid (4% yield) from methyl 4-bromo-3-hydroxythiophene-2-carboxylate and 4-methoxybenzyl chloride.

methyl 4-bromo-3-(4-methoxybenzyloxy)thiophene-2-carboxylate

¹ H-NMR(CDCl ₃ ) δ 7.42-7.50(2H, m), 7.39(1H, s), 6.87-6.94(2H, m), 5.14(2H, c), 3.88(3H, s), 3.82(3H, s).

4-bromo-3-(4-methoxybenzyloxy)thiophene-2-carboxylic acid

¹ H-NMR(DMSO-d ₆ ) δ 13.10-13.64(1H, br), 7.97(1H, s), 7.36-7.43(2H, m), 6.91 -6.98(2H, m), 5.10(2H, s), 3.76(3H, s).

3-bromo-4-(4-methoxybenzyloxy)thiophene

¹ H-NMR(CDCl ₃ ) δ 7.32-7.42(2H, m). 7.18(1H, d, J=3.5Hz), 6.88-6.97(2H, m), 6.28(1H, d, J=3.5Hz), 5.02(2H , s), 3.82(3H, s).

{[4-(4-methoxybenzyloxy)thiophen-3-yl]ethynyl}trimethylsilane

¹ H-NMR(CDCl ₃ ) δ 7.35-7.41(3H, m), 6.87-6.95(2H, m), 6.22(1H, d, J=3.3 Hz) , 5.02(2H, s), 3.82(3H, s), 0.24(9H, s).

3-ethynyl-4-(4-methoxybenzyloxy)thiophene

¹ H-NMR(CDCl ₃ ) δ 7.41 (1H, d, J=3.4 Hz), 7.34-7.40(2H, m), 6.88-6.94(2H, m) , 6.22(1H, d, J=3.3Hz), 5.03(2H, s), 3.81(3H, s), 3.16(1H, s).

3-{4-[4-(4-methoxybenzyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione

¹ H-NMR(DMSO-d ₆ ) δ 11.22(1H, s), 8.21(1H, s), 7.87(1H, d, J=3.4 Hz), 7.40-7 .47(2H, m), 6.92-6.99(2H, m), 6.82(1H, d, J=3.4 Hz), 5.84(1H, dd, J=5.0 , 12.4 Hz), 5.12(2H, s), 3.75(3H, s), 2.63-2.92(3H, m), 2.28-2.38(1H, m) .

[0224]

Example 32 (compound 32)

3-{4-[4-(benzyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione

In a manner similar to that of Example 27 (27-3, 27-4), 3-{4-[4-(benzyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl} was obtained piperidine-2,6-dione as a gray solid (29% yield) from 3-(benzyloxy)-4-bromothiophene-2-carboxylic acid.

3-(benzyloxy)-4-bromothiophene

¹ H-NMR(CDCl ₃ ) δ 7.42-7.48(2H, m), 7.36-7.42(2H, m), 7.30-7.36(1H, m), 7, 19(1H, d, J=3.5Hz), 6.27(1H, d, J=3.5Hz), 5.09(2H, s).

{[4-(benzyloxy)thiophen-3-yl]ethynyl}trimethylsilane

¹ H-NMR(CDCl ₃ ) δ 7.28-7.49(6H, m), 6.22(1H, d, J=3.3 Hz), 5.09(2H, s), 0.25 (9H, s).

3-(benzyloxy)-4-ethynylthiophene

¹ H-NMR(CDCl ₃ ) δ 7.29-7.47(6H, m), 6.22(1H, d, J=3.3 Hz), 5.11(2H, s), 3.18 (1H, s).

3-{4-[4-(benzyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione

¹ H-NMR(DMSO-d ₆ ) δ 11.23(1H, s), 8.28(1H, s), 7.89(1H, d, J=3.4 Hz), 7.47-7 .53(2H, m), 7.37-7.44(2H, m), 7.30-7.37(1H, m), 6.82(1H, d, J=3.4 Hz), 5.86(1H, dd, J=5.1, 12.4Hz), 5.22(2H, s), 2.64-2.93(3H, m), 2.29-2.39( 1H, m).

[0225]

Example 33 (compound 33)

3-{4-[4-(pyridin-4-ylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione

(33-1) 4-(bromomethyl)pyridine hydrobromide (2 00 g, 7.91 mmol), triethylamine (1.10 ml, 7.89 mmol) and cesium carbonate (2.58 g, 7.92 mmol) and the mixture was stirred under argon at 50°C for 20 h The reaction mixture was filtered, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrated residue was purified by column chromatography (dichloromethane/methanol) to give methyl 4-bromo-3-(pyridin-4-ylmethoxy)thiophene-2-carboxylate (0.27 g, 26%) as a brown solid.

¹ H-NMR(CDCl ₃ ) δ 8.55-8.75(2H, m), 7.46-7.50(2H, m), 7.44(1H, s), 5.24(2H, c), 3.87(3H, s).

[0226]

(33-2) Potassium hydroxide (85 %) (0.23 g, 3.48 mmol) and water (2.0 ml), and the mixture was refluxed for 15 hours. The reaction mixture was concentrated, water (6 ml) and 1.0 M hydrochloric acid (3.52 ml) and the mixture was stirred at room temperature for 10 minutes. The precipitate was collected by filtration and washed with water to give 4-bromo-3-(pyridin-4-ylmethoxy)thiophene-2-carboxylic acid (0.89 g, 98%) as a light brown solid. The resulting 4-bromo-3-(pyridin-4-ylmethoxy)thiophene-2-carboxylic acid was used for the next reaction without purification.

¹ H-NMR(DMSO-d ₆ ) δ 12.75-14.10(1H, br.), 8.52-8.69(2H, br.), 8.03(1H, s), 7, 51(2H, d, J=5.1 Hz), 5.24(2H, s).

[0227]

(33-3) Powdered copper (0.21 g, 3.30 mmol) and the mixture was stirred under argon at 150°C for 15 min. The reaction mixture was filtered through celite and the filtrate was concentrated. The concentrated residue was purified by column chromatography (hexane/ethyl acetate) to give 4-[(4-bromothiophen-3-yloxy)methyl]pyridine (0.69 g, 90%) as a brown solid.

¹ H-NMR(CDCl ₃ ) δ 8.50-8.75(2H, br), 7.39(2H, brd, J=5.0 Hz), 7.24(1H, d, J=3 .4 Hz), 6.27(1H, d, J=3.5 Hz), 5.11(2H, s).

[0228]

(33-4) In a manner similar to that of Example 11, 3-{4-[4-(pyridin-4-ylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl} was obtained piperidin-2,6-dione as a gray solid (10% yield) from 4-[(4-bromothiophen-3-yloxy)methyl]pyridine.

4-({4-[(trimethylsilyl)ethynyl]thiophen-3-yloxy}methyl)pyridine

¹ H-NMR(CDCl ₃ ) δ 8.50-8.75(2H, br), 7.37-7.43(2H, br), 7.40(1H, d, J=3.3 Hz), 6.22(1H, d, J=3.3 Hz), 5.10(2H, s), 0.27(9H, s).

4-[(4-ethynylthiophen-3-yloxy)methyl]pyridine

¹ H-NMR(CDCl ₃ ) δ 8.58-8.68(2H, m), 7.45(1H, d, J=3.4 Hz), 7.35-7.40(2H, m) , 6.21(1H, d, J=3.3Hz), 5.12(2H, s), 3.21(1H, s).

3-{4-[4-(pyridin-4-ylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione

¹ H-NMR(DMSO-d ₆ ) δ 11.24(1H, s), 8.20-9.55(2H, br), 8.36(1H, s), 7.90(1H, d , J=3.4 Hz), 7.23-7.86(2H, broad), 6.81(1H, d, J=3.4 Hz), 5.88(1H, dd, J=5 .3, 12.6 Hz), 5.25(2H, br s), 2.65-2.94(3H, m), 2.29-2.40(1H, m).

[0229]

Example 34 (compound 34)

3-{4-[4-(pyridin-2-ylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione

In a manner similar to that of Example 33, 3-{4-[4-(pyridin-2-ylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidin-2,6 was obtained -dione as a gray solid (23% yield) from methyl 4-bromo-3-hydroxythiophene-2-carboxylate and 2-(bromomethyl)pyridine hydrobromide.

methyl 4-bromo-3-(pyridin-2-ylmethoxy)thiophene-2-carboxylate

¹ H-NMR(CDCl ₃ ) δ 8.55-8.63(1H, m), 7.74-7.87(2H, m), 7.43(1H, s), 7.22-7, 28(1H, m), 5.33(2H, s), 3.85(3H, s).

4-bromo-3-(pyridin-2-ylmethoxy)thiophene-2-carboxylic acid

¹ H-NMR(DMSO-d ₆ ) δ 12.96-13.89(1H, br), 8.51-8.57(1H, m), 8.01(1H, s), 7.88 (1H, dt, J=1.8, 7.7 Hz), 7.69-7.74(1H, m), 7.34-7.40(1H, m), 5.27(2H, s ).

2-[(4-bromothiophen-3-yloxy)methyl]pyridine

¹ H-NMR(CDCl ₃ ) δ 8.55-8.62(1H, m), 7.75(1H, dt, J=1.7, 7.7 Hz), 7.58-7.64( 1H, m), 7.20-7.27(2H, m), 6.32(1H, d, J=3.5 Hz), 5.23(2H, s).

2-({4-[(trimethylsilyl)ethynyl]thiophen-3-yloxy}methyl)pyridine

¹ H-NMR(CDCl ₃ ) δ 8.54-8.62(1H, m), 7.73(1H, dt, J=1.7, 7.7 Hz), 7.63-7.68( 1H, m), 7.39(1H, d, J=3.3 Hz), 7.20-7.25(1H, m), 6.26(1H, d, J=3.3 Hz), 5.21(2H, s), 0.27(9H, s).

2-[(4-ethynylthiophen-3-yloxy)methyl]pyridine

¹ H-NMR(CDCl ₃ ) δ 8.54-8.64(1H, m), 7.73(1H, dt, J=1.7, 7.7 Hz), 7.56-7.64( 1H, m), 7.43(1H, d, J=3.4 Hz), 7.20-7.25(1H, m), 6.26(1H, d, J=3.4 Hz), 5.24(2H, s), 3.22(1H, s).

3-{4-[4-(pyridin-2-ylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione

¹ H-NMR(DMSO-d ₆ ) δ 11.24(1H, br s), 8.60(1H, d, J=4.4 Hz), 8.41(1H, s), 7.90 (1H, d, J=3.4 Hz), 7.84(1H, dt, J=1.7, 7.7 Hz), 7.54(1H, d, J=7.8 Hz), 7 .36(1H, dd, J=5.0, 6.8 Hz), 6.82(1H, d, J=3.4 Hz), 5.88(1H, dd, J=5.2, 12 .5 Hz), 5.29(2H, s), 2.81-2.94(1H, m), 2.64-2.81(2H, m), 2.30-2.40(1H, m).

[0230]

Example 35 (compound 35)

3-{4-[4-(pyridin-3-ylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione

In a manner similar to that of Example 33, 3-{4-[4-(pyridin-3-ylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidin-2,6 was obtained -dione as a gray solid (5% yield) from methyl 4-bromo-3-hydroxythiophene-2-carboxylate and 3-(bromomethyl)pyridine hydrobromide.

methyl 4-bromo-3-(pyridin-3-ylmethoxy)thiophene-2-carboxylate

¹ H-NMR(CDCl ₃ ) δ 8.70-8.78(1H, br), 8.57-8.64(1H, m), 7.91-7.97(1H, m), 7 .42(1H, s), 7.31-7.38(1H, m), 5.24(2H, s), 3.89(3H, s).

4-bromo-3-(pyridin-3-ylmethoxy)thiophene-2-carboxylic acid

¹ H-NMR (DMSO-d ₆ ) δ 13.15-13.76(1H, br.), 8.67(1H, br. s), 8.53-8.61(1H, m), 8 .00(1H, s), 7.87-7.93(1H, m), 7.44(1H, ddd, J=0.4, 4.8, 7.8 Hz), 5.23(2H , With).

3-[(4-bromothiophen-3-yloxy)methyl]pyridine

¹ H-NMR(CDCl ₃ ) δ 8.66-8.75(1H, m), 8.56-8.64(1H, m), 7.79-7.87(1H, m), 7, 35(1H, ddd, J=0.4, 4.9, 7.8Hz), 7.22(1H, d, J=3.4Hz), 6.33(1H, d, J=3, 5 Hz), 5.11(2H, s).

3-({4-[(trimethylsilyl)ethynyl]thiophen-3-yloxy}methyl)pyridine

¹ H-NMR(CDCl ₃ ) δ 8.66-8.74(1H, br), 8.54-8.63(1H, m), 7.80-7.87(1H, m), 7 .39(1H, d, J=3.3Hz), 7.33(1H, dd, J=4.9, 7.7Hz), 6.28(1H, d, J=3.3Hz) . 5.11(2H, s), 0.24(9H, s).

3-[(4-ethynylthiophen-3-yloxy)methyl]pyridine

¹ H-NMR(CDCl ₃ ) δ 8.67-8.73(1H, m), 8.59(1H, dd, J=1.6, 4.8 Hz), 7.78-7.83( 1H, m), 7.44(1H, d, J=3.3 Hz), 7.33(1H, ddd, J=0.6, 4.8, 7.8 Hz), 6.28(1H , d, J=3.3 Hz), 5.12(2H, s), 3.17(1H, s).

3-{4-[4-(pyridin-3-ylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione

¹ H-NMR(DMSO-d ₆ ) δ 11.23(1H, s), 8.73(1H, d, J=1.7 Hz), 8.55(1H, dd, J=1.6 , 4.8 Hz), 8.27(1H, s), 7.90-7.94(1H, m), 7.89(1H, d, J=3.4 Hz), 7.43(1H , ddd, J=0.7, 4.8, 7.8 Hz), 6.89(1H, d, J=3.4 Hz), 5.85(1H, dd, J=5.2, 12 .5 Hz), 5.26(2H, s), 2.79-2.92(1H, m), 2.63-2.79(2H, m), 2.26-2.39(1H, m).

[0231]

Example 36 (compound 36)

3-(4-{4-[4-(morpholinomethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione (36-1) K a solution of methyl 4-bromo-3-hydroxythiophene-2-carboxylate (1.00 g, 4.22 mmol) in acetonitrile (50 ml) was added α,α'-dibromo-p-xylene (3.34 g, 12.65 mmol) and potassium carbonate (0.58 g, 4.20 mmol) and the mixture was stirred under argon atmosphere at 50° C. for 15 h. The reaction mixture was concentrated, saturated brine was added to the concentrated residue, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrated residue was purified by column chromatography (hexane/ethyl acetate) to give methyl 4-bromo-3-[4-(bromomethyl)benzyloxy]thiophene-2-carboxylate (1.30 g, 73%) as a light brown solid.

¹ H-NMR(CDCl ₃ ) δ 7.50-7.56(2H, m), 7.39-7.45(3H, m), 5.20(2H, s), 4.51(2H, c), 3.87(3H, s).

[0232]

(36-2) Morpholine (0.89 ml, 10.17 mmol) and the mixture was stirred under argon at room temperature for 20 hours. The reaction mixture was filtered and the filtrate was concentrated. The concentrated residue was dissolved in ethyl acetate, washed with water, dried over anhydrous magnesium sulfate and concentrated. The concentrated residue was purified by column chromatography (hexane/ethyl acetate) to obtain a mixture of methyl 4-bromo-3-[4-(morpholinomethyl)benzyloxy]thiophene-2-carboxylate (2.15 g) as a light yellow oil. The resulting mixture of methyl 4-bromo-3-[4-(morpholinomethyl)benzyloxy]thiophene-2-carboxylate was used for the next step without further purification.

¹ H-NMR(CDCl ₃ ) δ 7.50(2H, d, J=8.0 Hz), 7.40(1H, s), 7.35(2H, d, J=8.0 Hz), 5.18(2H, s), 3.88(3H, s), 3.66-3.78(4H, m), 3.51(2H, s), 2.41-2.48(4H, m).

[0233]

(36-3) In a manner similar to that of Example 33 (33-2, 33-3), 4-{4-[(4-bromothiophen-3-yloxy)methyl]benzyl}morpholine was obtained as a red-brown oil ( yield 89%) from a mixture of methyl 4-bromo-3-[4-(morpholinomethyl)benzyloxy]thiophene-2-carboxylate.

4-bromo-3-[4-(morpholinomethyl)benzyloxy]thiophene-2-carboxylic acid

¹ H-NMR(DMSO-d ₆ ) δ 7.97(1H, s), 7.44(2H, d, J=8.0 Hz), 7.33(2H, d, J=8.0 Hz ), 5.15(2H, s), 3.54-3.62(4H, m), 3.50(2H, s), 2.34-2.42(4H, m).

4-{4-[(4-bromothiophen-3-yloxy)methyl]benzyl}morpholine

¹ H-NMR(CDCl ₃ ) δ 7.40(2H, d, J=8.2 Hz), 7.35(2H, d, J=8.2 Hz), 7.20(1H, d, J =3.5 Hz), 6.28(1H, d, J=3.5 Hz), 5.07(2H, s), 3.68-3.73(4H, m), 3.50(2H , c), 2.42-2.48(4H, m).

[0234]

(36-4) Triethylamine (0 .89 ml, 6.39 mmol), tetrakis(triphenylphosphine)palladium (0) (0.24 g, 0.21 mmol), copper (I) iodide (0.12 g, 0.63 mmol) and trimethylsilylacetylene (0 .64 ml, 4.63 mmol) and the mixture was sealed in a test tube under argon and stirred at 60° C. for 4 days. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrated residue was purified by column chromatography (hexane/ethyl acetate) to give 4-[4-({4-[(trimethylsilyl)ethynyl]thiophen-3-yloxy}methyl)benzyl]morpholine (0.63 g, 38%) as brown oils.

¹ H-NMR(CDCl ₃ ) δ 7.41(2H, d, J=8.1 Hz), 7.37(1H, d, J=3.3 Hz), 7.33(2H, d, J =8.1Hz), 6.23(1H, d, J=3.3Hz), 5.07(2H, s), 3.68-3.74(4H, m), 3.51(2H , s), 2.41-2.48(4H, m), 0.24(9H, s).

[0235]

(36-5) In a manner similar to that of Example 8 (8-2, 8-3), 3-(4-{4-[4-(morpholinomethyl)benzyloxy]thiophen-3-yl}-1H-1, 2,3-triazol-1-yl)piperidin-2,6-dione as brown solid (50% yield) from 4-[4-({4-[(trimethylsilyl)ethynyl]thiophen-3-yloxy}methyl )benzyl]morpholine.

4-{4-[(4-ethynylthiophen-3-yloxy)methyl]benzyl}morpholine

¹ H-NMR(CDCl ₃ ) δ 7.42(1H, d, J=3.4 Hz), 7.40(2H, d, J=8.3 Hz), 7.34(2H, d, J =8.2 Hz), 6.22(1H, d, J=3.3 Hz), 5.09(2H, s), 3.71(4H, br. t, J=4.7 Hz), 3.50(2H, s), 3.17(1H, s), 2.45(4H, brt, J=4.5 Hz).

3-(4-{4-[4-(morpholinomethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione

¹ H-NMR(DMSO-d ₆ ) δ 11.23(1H, s), 8.27(1H, s), 7.88(1H, d, J=3.4 Hz), 7.45(2H , d, J=8.0 Hz), 7.33(2H, d, J=8.1 Hz), 6.82(1H, d, J=3.4 Hz), 5.86(1H, dd , J=5.0, 12.3 Hz), 5.20(2H, s), 3.56(4H, br. t, J=4.6 Hz), 3.45(2H, s), 2 .65-2.92(3H, m), 2.29-2.39(5H, m).

[0236]

(36-6) To a suspension of 3-(4-{4-[4-(morpholinomethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidin-2,6- dione (0.10 g, 0.21 mmol) in acetone (5 mL) methanesulfonic acid (13.9 μL, 0.21 mmol) was added and the mixture was stirred at room temperature for 15.5 h. The precipitate was collected by filtration and washed acetone to give 3-(4-{4-[4-(morpholinomethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidin-2,6-dione methanesulfonate (0 .10 g, 86%) as a light brown solid.

¹ H-NMR (DMSO-d ₆ ) δ 11.25(1H, s), 9.70-9.86(1H, br), 8.34(1H, s), 7.89(1H, d , J=3.4 Hz), 7.61(2H, d, J=7.8 Hz), 7.52(2H, d, J=7.8 Hz), 6.82(1H, d, J =3.4 Hz), 5.87(1H, dd, J=5.2, 12.6 Hz), 5.27(2H, br s), 4.36(2H, br d, J= 4.8 Hz), 3.96(2H, br. d, J=11.9 Hz), 3.61(2H, br. t, J=12.0 Hz), 3.26(2H, br. d, J=11.6 Hz), 3.05-3.18(2H, m), 2.81-2.94(1H, m), 2.65-2.81(2H, m), 2 .28-2.39(4H, m).

[0237]

Example 37 (compound 37)

3-(4-{4-[4-(methoxymethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione

(37-1) To a solution of methyl 4-bromo-3-[4-(bromomethyl)benzyloxy]thiophene-2-carboxylate (synthesized by the method according to example 36 (36-1)) (2.71 g, 6.45 mmol) in methanol (11 ml) was added potassium hydroxide (85%) (0.52 g, 7.88 mmol) and water (4.5 ml) and the mixture was refluxed. After 2 h, potassium hydroxide (85%) (0.74 g, 11.21 mmol) was added and the mixture was further refluxed for 1 h. The reaction mixture was concentrated, to the concentrated residue were added water (20 ml) and 2.0 M hydrochloric acid (10.0 ml) and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give a mixture of 4-bromo-3-[4-(methoxymethyl)benzyloxy]thiophene-2-carboxylic acid (2.26 g) as a tan solid. The resulting mixture of 4-bromo-3-[4-(methoxymethyl)benzyloxy]thiophene-2-carboxylic acid was used for the next reaction without purification.

¹ H-NMR(CDCl ₃ ) δ 7.52(1H, s), 7.49(2H, d, J=7.9 Hz), 7.37(2H, d, J=8.1 Hz), 5.27(2H, s), 4.48(2H, s), 3.39(3H, s).

[0238]

(37-2) Silver carbonate (0.17 g, 0 .62 mmol) and acetic acid (0.38 ml, 6.64 mmol) and the mixture was stirred under argon at 120° C. for 30 min. Ethyl acetate was added to the reaction mixture, and the mixture was filtered. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrated residue was purified by column chromatography (hexane/ethyl acetate) to give 3-bromo-4-[4-(methoxymethyl)benzyloxy]thiophene (1.39 g, 2 steps, 69%) as a light brown solid.

¹ H-NMR(CDCl ₃ ) δ 7.43(2H, d, J=8.2 Hz), 7.36(2H, d, J=8.2 Hz), 7.19(1H, d, J =3.5 Hz), 6.26(1H, d, J=3.5 Hz), 5.08(2H, s), 4.47(2H, s), 3.40(3H, s).

[0239]

(37-3) In a manner similar to that of Example 11, 3-(4-{4-[4-(methoxymethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl was obtained )piperidine-2,6-dione as a white solid (47% yield) from 3-bromo-4-[4-(methoxymethyl)benzyloxy]thiophene.

({4-[4-(methoxymethyl)benzyloxy]thiophen-3-yl}ethynyl)trimethylsilane

¹ H-NMR(CDCl ₃ ) δ 7.45(2H, d, J=8.2 Hz), 7.37(1H, d, J=3.3 Hz), 7.34(2H, d, J =8.2 Hz), 6.21(1H, d, J=3.3 Hz), 5.09(2H, s), 4.47(2H, s), 3.39(3H, s), 0.25(9H, s).

3-ethynyl-4-[4-(methoxymethyl)benzyloxy]thiophene

¹ H-NMR(CDCl ₃ ) δ 7.43(2H, d, J=8.3 Hz), 7.41(1H, d, J=3.4 Hz), 7.35(2H, d, J =8.2 Hz), 6.21(1H, d, J=3.3 Hz), 5.10(2H, s), 4.46(2H, s), 3.39(3H, s), 3.17(1H, s).

3-(4-{4-[4-(methoxymethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione

¹ H-NMR(DMSO-d ₆ ) δ 11.23(1H, br s), 8.27(1H, s), 7.88(1H, d, J=3.4 Hz), 7.48 (2H, d, J=8.1 Hz), 7.34(2H, d, J=8.1 Hz), 6.81(1H, d, J=3.4 Hz), 5.86(1H , dd, J=5.1, 12.5 Hz), 5.21(2H, s), 4.41(2H, s), 3.29(3H, s), 2.63-2.93( 3H, m), 2.29-2.39(1H, m).

[0240]

Example 38 (compound 38)

3-{4-[4-(4-{[(2S,6R)-2,6-dimethylmorpholino]methyl}benzyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl} piperidine-2,6-dione

(38-1) In a manner similar to that of Example 36(36-1, 36-2) and Example 33(33-2), 4-bromo-3-(4-{[(2S,6R)-2, 6-dimethylmorpholino]methyl}benzyloxy)thiophene-2-carboxylic acid as light yellow solid (71% yield) from methyl 4-bromo-3-hydroxythiophene-2-carboxylate, α,α'-dibromo-p-xylene and cis-2,6-dimethylmorpholine.

methyl 4-bromo-3-(4-{[(2S,6R)-2,6-dimethylmorpholino]methyl}benzyloxy)thiophene-2-carboxylate

¹ H-NMR(CDCl ₃ ) δ 7.51(2H, d, J=8.0 Hz), 7.41(1H, s), 7.34(2H, d, J=8.0 Hz), 5.18(2H, s), 3.88(3H, s), 3.64-3.73(2H, m), 3.48(2H, s), 2.66-2.74(2H, m), 1.74(2H, br. t, J=10.8 Hz), 1.14(6H, d, J=6.3 Hz).

4-bromo-3-(4-{[(2S,6R)-2,6-dimethylmorpholino]methyl}benzyloxy)thiophene-2-carboxylic acid

¹ H-NMR(CDCl ₃ ) δ 7.46(2H, d, J=8.1 Hz), 7.41(2H, d, J=8.1 Hz), 7.29(1H, s), 5.31(2H, s), 3.95-4.03(2H, m), 3.93(2H, s), 3.18(2H, d, J=11.1Hz), 2.13 (2H, br. t, J=11.3 Hz), 1.16(6H, d, J=6.3 Hz).

[0241]

(38-2) To a solution of 4-bromo-3-(4-{[(2S,6R)-2,6-dimethylmorpholino]methyl}benzyloxy)thiophene-2-carboxylic acid (1.44 g, 3.27 mmol ) in dimethyl sulfoxide (7.5 ml) were added silver carbonate (186 mg, 0.67 mmol) and acetic acid (0.22 ml, 3.84 mmol) and the mixture was stirred at 120°C for 1.5 h. 1.0 M hydrochloric acid was added to the reaction mixture, and the mixture was neutralized with a saturated sodium bicarbonate aqueous solution. The mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give (2S,6R)-4-{4-[(4-bromothiophen-3-yloxy)methyl]benzyl}-2,6-dimethylmorpholine (1.29 g, 99% ) as a brown oil. The resulting (2S,6R)-4-{4-[(4-bromothiophen-3-yloxy)methyl]benzyl}-2,6-dimethylmorpholine was used for the next reaction without purification.

¹ H-NMR(CDCl ₃ ) δ 7.40(2H, d, J=8.1 Hz), 7.34(2H, d, J=8.1 Hz), 7.19(1H, d, J =3.5 Hz), 6.28(1H, d, J=3.5 Hz), 5.07(2H, s), 3.64-3.74(2H, m), 3.47(2H , s), 2.66-2.74(2H, m), 1.75(2H, dd, J=10.3, 11.2 Hz), 1.13(6H, d, J=6.3 Hz).

[0242]

(38-3) In a manner similar to that of Example 36 (36-4, 36-5), 3-{4-[4-(4-{[(2S,6R)-2,6-dimethylmorpholino]methyl} was obtained benzyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidin-2,6-dione as white solid (53% yield) from (2S,6R)-4-{ 4-[(4-bromothiophen-3-yloxy)methyl]benzyl}-2,6-dimethylmorpholine.

(2S,6R)-2,6-dimethyl-4-[4-({4-[(trimethylsilyl)ethynyl]thiophen-3-yloxy}methyl)benzyl]morpholine

¹ H-NMR(CDCl ₃ ) δ 7.41(2H, d, J=8.1 Hz), 7.37(1H, d, J=3.3 Hz), 7.33(2H, d, J =8.1Hz), 6.23(1H, d, J=3.3Hz), 5.07(2H, s), 3.64-3.74(2H, m), 3.49(2H , s), 2.70(2H, broad d, J=10.6 Hz), 1.75(2H, t, J=10.7 Hz), 1.13(6H, d, J=6, 3 Hz), 0.24(9H, s).

(2S,6R)-4-{4-[(4-ethynylthiophen-3-yloxy)methyl]benzyl}-2,6-dimethylmorpholine

¹ H-NMR(CDCl ₃ ) δ 7.30-7.42(5H, m), 6.23(1H, d, J=3.3 Hz), 5.08(2H, s), 3.64 -3.73(2H, m), 3.47(2H, s), 3.17(1H, s), 2.66-2.73(2H, m), 1.74(2H, dd, J =10.5, 11.1 Hz), 1.13(6H, d, J=6.3 Hz).

3-{4-[4-(4-{[(2S,6R)-2,6-dimethylmorpholino]methyl}benzyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl} piperidine-2,6-dione

¹ H-NMR(CDCl ₃ ) δ 8.84-9.26(1H, br), 7.94(1H, s), 7.91(1H, d, J=3.4 Hz), 7, 40(2H, d, J=8.1Hz), 7.34(2H, d, J=8.1Hz), 6.41(1H, d, J=3.4Hz), 5.31( 1H, dd, J=5.2, 10.2 Hz), 5.09 and 5.13(2H, ABq, J=11.1 Hz), 3.62-3.74(2H, m), 3 .46 and 3.57(2H, ABq, J=13.0 Hz), 2.89-3.01(1H, m), 2.54-2.84(5H, m), 1.85(1H , t, J=10.8 Hz), 1.77(1H, t, J=10.8 Hz), 1.15(3H, d, J=6.4 Hz), 1.14(3H, d , J=6.4 Hz).

[0243]

Example 39 (compound 39)

3-(4-{4-[3-(morpholinomethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione

In a manner similar to that of Example 38, 3-(4-{4-[3-(morpholinomethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidin-2, 6-dione as a blue solid (10% yield) from methyl 4-bromo-3-hydroxythiophene-2-carboxylate, α,α'-dibromo-m-xylene and morpholine.

methyl 4-bromo-3-[3-(bromomethyl)benzyloxy]thiophene-2-carboxylate

¹ H-NMR(CDCl ₃ ) δ 7.56-7.59(1H, br s), 7.45-7.50(1H, m), 7.41(1H, s), 7.36- 7.40(2H, m), 5.20(2H, s), 4.52(2H, s), 3.88(3H, s).

methyl 4-bromo-3-[3-(morpholinomethyl)benzyloxy]thiophene-2-carboxylate

¹ H-NMR(CDCl ₃ ) δ 7.42-7.48(2H, m), 7.39(1H, s), 7.29-7.37(2H, m), 5.21(2H, c), 3.88(3H, s), 3.71(4H, br. t, J=4.7 Hz), 3.52(2H, s), 2.44(4H, br. t, J =4.5 Hz).

4-bromo-3-[3-(morpholinomethyl)benzyloxy]thiophene-2-carboxylic acid

¹ H-NMR(CDCl ₃ ) δ 11.07-11.47(1H, br s), 7.54-7.62(1H, br s), 7.50(1H, br d, J =6.8 Hz), 7.22-7.35(3H, m), 5.22(2H, s), 3.92(2H, s), 3.82(4H, brt, J= 4.6 Hz), 2.71-2.95(4H, br).

4-{3-[(4-bromothiophen-3-yloxy)methyl]benzyl}morpholine

¹ H-NMR(CDCl ₃ ) δ 7.39-7.42(1H, br s), 7.26-7.37(3H, m), 7.19(1H, d, J=3.5 Hz), 6.27(1H, d, J=3.5 Hz), 5.08(2H, s), 3.70(4H, br. t, J=4.7 Hz), 3.51( 2H, s), 2.44(4H, br. t, J=4.5 Hz).

4-[3-({4-[(trimethylsilyl)ethynyl]thiophen-3-yloxy}methyl)benzyl]morpholine

¹ H-NMR(CDCl ₃ ) δ 7.39-7.42(1H, br), 7.27-7.39(4H, m), 6.22(1H, d, J=3.3 Hz ), 5.08(2H, s), 3.70(4H, br. t, J=4.6 Hz), 3.51(2H, s), 2.43(4H, br. t, J= 4.5 Hz), 0.25(9H, s).

4-{3-[(4-ethynylthiophen-3-yloxy)methyl]benzyl}morpholine

¹ H-NMR(CDCl ₃ ) δ 7.39-7.43(2H, m), 7.27-7.37(3H, m), 6.21(1H, d, J=3.3 Hz) , 5.10(2H, s), 3.70(4H, broad t, J=4.6 Hz), 3.51(2H, s), 3.17(1H, s), 2.43( 4H, broad t, J=4.5 Hz).

3-(4-{4-[3-(morpholinomethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione

¹ H-NMR(DMSO-d ₆ ) δ 11.16-11.30(1H, br), 8.27(1H, s), 7.88(1H, d, J=3.4 Hz), 7.31-7.43(3H, m), 7.26(1H, brd, J=7.2Hz), 6.80(1H, d, J=3.4Hz), 5.85 (1H, dd, J=5.1, 12.4 Hz), 5.22(2H, s), 3.53(4H, brt, J=4.5 Hz), 3.46(2H, c), 2.63-2.94(3H, m), 2.21-2.41(5H, m).

[0244]

Example 40 (compound 40)

3-(4-{4-[2-(morpholinomethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione

(40-1) In a manner similar to that of Example 38 (38-1, 38-2), 4-{2-[(4-bromothiophen-3-yloxy)methyl]benzyl}morpholine was obtained as a brown oil (yield 64 %) from methyl 4-bromo-3-hydroxythiophene-2-carboxylate, α,α'-dibromo-o-xylene and morpholine.

methyl 4-bromo-3-[2-(bromomethyl)benzyloxy]thiophene-2-carboxylate

¹ H-NMR(CDCl ₃ ) δ 7.56-7.62(1H, m), 7.41-7.46(2H, m), 7.34-7.39(2H, m), 5, 32(2H, s), 4.86(2H, s), 3.90(3H, s).

methyl 4-bromo-3-[2-(morpholinomethyl)benzyloxy]thiophene-2-carboxylate

¹ H-NMR(CDCl ₃ ) δ 7.63-7.69(1H, m), 7.41(1H, s), 7.24-7.35(3H, m), 5.42(2H, c), 3.86(3H, s), 3.66(2H, s), 3.64(4H, br. t, J=4.6 Hz), 2.43(4H, br. t, J =4.4 Hz).

4-{2-[(4-bromothiophen-3-yloxy)methyl]benzyl}morpholine

¹ H-NMR(CDCl ₃ ) δ 7.50(1H, brd, J=6.6 Hz), 7.22-7.34(3H, m), 7.18(1H, d, J= 3.5 Hz), 6.35(1H, d, J=3.5 Hz), 5.29(2H, s), 3.64(4H, br. t, J=4.6 Hz), 3 .57(2H, s), 2.41(4H, br. t, J=4.4 Hz).

[0245]

(40-2) To a solution of 4-{2-[(4-bromothiophen-3-yloxy)methyl]benzyl}morpholine (680.2 mg, 1.85 mmol) in N,N-dimethylformamide (3.5 ml) bis(triphenylphosphine)palladium(II) chloride (128.6 mg, 0.18 mmol), triethylamine (1.52 ml, 10.91 mmol) and trimethylsilylacetylene (1.25 ml, 9.04 mmol) were added and the mixture stirred under argon atmosphere at 70° C. for 6.5 hours. The reaction mixture was diluted with ethyl acetate, saturated aqueous ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrated residue was purified by column chromatography (hexane/ethyl acetate) to give 4-[2-({4-[(trimethylsilyl)ethynyl]thiophen-3-yloxy}methyl)benzyl]morpholine (602.8 mg, 84%) as red - brown butter.

¹ H-NMR(CDCl ₃ ) δ 7.57(1H, brd, J=7.1 Hz), 7.37(1H, d, J=3.3 Hz), 7.22-7.34 (3H, m), 6.26(1H, d, J=3.3Hz), 5.29(2H, s), 3.61-3.68(4H, m), 3.59(2H, c), 2.36-2.47(4H, m), 0.23(9H, s).

[0246]

(40-3) In a manner similar to that of Example 8 (8-2, 8-3), 3-(4-{4-[2-(morpholinomethyl)benzyloxy]thiophen-3-yl}-1H-1, 2,3-triazol-1-yl)piperidin-2,6-dione as a bluish white solid (40% yield) from 4-[2-({4-[(trimethylsilyl)ethynyl]thiophen-3-yloxy }methyl)benzyl]morpholine.

4-{2-[(4-ethynylthiophen-3-yloxy)methyl]benzyl}morpholine

¹ H-NMR(CDCl ₃ ) δ 7.48-7.53(1H, m), 7.42(1H, d, J=3.3 Hz), 7.23-7.33(3H, m) , 6.31(1H, d, J=3.3 Hz), 5.31(2H, s), 3.65(4H, br. t, J=4.6 Hz), 3.58(2H, c), 3.16(1H, s), 2.42(4H, br. t, J=4.4 Hz).

3-(4-{4-[2-(morpholinomethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione

¹ H-NMR(DMSO-d ₆ ) δ 11.18-11.26(1H, br), 8.25(1H, s), 7.89(1H, d, J=3.4 Hz), 7.45-7.52(1H, m), 7.25-7.36(3H, m), 6.83(1H, d, J=3.4 Hz), 5.85(1H, dd, J=5.0, 12.4 Hz), 5.38(2H, s), 3.55(2H, s), 3.51(4H, brt, J=4.3 Hz), 2, 63-2.91(3H, m), 2.24-2.41(5H, m).

[0247]

Example 41 (Compound 41)

3-(4-{4-[4-(pyrrolidin-1-ylmethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidin-2,6-dione hydrochloride

In a manner similar to that of Example 38(38-1, 38-2) and Example 11, 3-(4-{4-[4-(pyrrolidin-1-ylmethyl)benzyloxy]thiophen-3-yl}-1H- 1,2,3-triazol-1-yl)piperidine-2,6-dione as red-brown oil (18% yield) from methyl 4-bromo-3-hydroxythiophene-2-carboxylate, α,α'-dibromo -p-xylene and pyrrolidine.

To a solution of the resulting 3-(4-{4-[4-(pyrrolidin-1-ylmethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidin-2,6- dione (316.9 mg, 0.70 mmol) in ethyl acetate (2 ml) was added 4.0 M hydrochloric acid/ethyl acetate solution (193.0 μl) at 0°C and the mixture was stirred at 0°C for 1 h. The precipitate was collected by filtration and the residue was recrystallized from acetone-methanol to give 3-(4-{4-[4-(pyrrolidin-1-ylmethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazole hydrochloride -1-yl)piperidin-2,6-dione (159.1 mg, 47%) as a light brown solid.

methyl 4-bromo-3-[4-(pyrrolidin-1-ylmethyl)benzyloxy]thiophene-2-carboxylate

¹ H-NMR(CDCl ₃ ) δ 7.46-7.58(4H, m), 7.41(1H, s), 5.20(2H, s), 3.88(5H, s), 2 .69-3.00(4H, br), 1.85-2.09(4H, br).

4-bromo-3-[4-(pyrrolidin-1-ylmethyl)benzyloxy]thiophene-2-carboxylic acid

MS m/z 398[M+1] ⁺ , 396[M+1] ⁺

1-{4-[(4-bromothiophen-3-yloxy)methyl]benzyl}pyrrolidine

¹ H-NMR(CDCl ₃ ) δ 7.32-7.45(4H, m), 7.19(1H, d, J=3.5 Hz), 6.27(1H, d, J=3, 5 Hz), 5.07(2H, s), 3.62(2H, s), 2.47-2.56(4H, m), 1.75-1.84(4H, m).

1-[4-({4-[(trimethylsilyl)ethynyl]thiophen-3-yloxy}methyl)benzyl]pyrrolidine

¹ H-NMR(CDCl ₃ ) δ 7.31-7.42(5H, m), 6.22(1H, d, J=3.3 Hz), 5.07(2H, s), 3.62 (2H, s), 2.47-2.54(4H, m), 1.74-1.84(4H, m), 0.24(9H, s).

1-{4-[(4-ethynylthiophen-3-yloxy)methyl]benzyl}pyrrolidine

¹ H-NMR(CDCl ₃ ) δ 7.30-7.44(5H, m), 6.22(1H, d, J=3.4 Hz), 5.09(2H, s), 3.61 (2H, s), 3.17(1H, s), 2.45-2.56(4H, m), 1.73-1.84(4H, m).

3-(4-{4-[4-(pyrrolidin-1-ylmethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidin-2,6-dione hydrochloride

¹ H-NMR(DMSO-d ₆ ) δ 11.22(1H, s), 10.82-10.99(1H, br), 8.31(1H, s), 7.88(1H, d , J=3.4 Hz), 7.53-7.66(4H, m), 6.83(1H, d, J=3.4 Hz), 5.89(1H, dd, J=5, 0, 12.4 Hz), 5.25(2H, s), 4.32(2H, d, J=5.8 Hz), 3.26-3.39(2H, m), 2.96- 3.10(2H, m), 2.81-2.95(1H, m), 2.65-2.81(2H, m), 2.29-2.39(1H, m), 1, 94-2.07(2H, m), 1.79-1.94(2H, m).

[0248]

Example 42 (compound 42)

3-(4-{4-[4-(piperidin-1-ylmethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidin-2,6-dione hydrochloride

(42-1) To a suspension of methyl 4-bromo-3-[4-(bromomethyl)benzyloxy]thiophene-2-carboxylate (synthesized by the method according to example 36 (36-1)) (1.17 g, 2.78 mmol) in water (7 ml) were added potassium hydroxide (85%) (0.53 g, 8.03 mmol) and acetone (5 ml) and the mixture was refluxed for 3 hours. The reaction mixture was concentrated, water was added to the concentrated residue and the mixture was washed with diethyl ether. 2.0 M hydrochloric acid (5.0 ml) was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 4-bromo-3-[4-(hydroxymethyl)benzyloxy]thiophene-2-carboxylic acid (0.94 g, 99%) as a white solid.

¹ H-NMR(CD ₃ OD) δ 7.66(1H, s), 7.46-7.52(2H, m), 7.32-7.37(2H, m), 5.20(2H , s), 4.61(2H, s).

[0249]

(42-2) In a manner similar to that of Example 37 (37-2), {4-[(4-bromothiophen-3-yloxy)methyl]phenyl}methanol (0.67 g, 82%) was obtained as a brown solid substances from 4-bromo-3-[4-(hydroxymethyl)benzyloxy]thiophene-2-carboxylic acid (0.94 g, 2.74 mmol).

¹ H-NMR(CDCl ₃ ) δ 7.37-7.47(4H, m), 7.20(1H, d, J=3.5 Hz), 6.27(1H, d, J=3, 5 Hz), 5.09(2H, s), 4.72(2H, d, J=5.8 Hz), 1.65(1H, t, J=5.9 Hz).

[0250]

(42-3) To a solution of {4-[(4-bromothiophen-3-yloxy)methyl]phenyl}methanol (0.67 g, 2.24 mmol) and triethylamine (0.62 ml, 4.45 mmol) in dichloromethane (9 ml) was added dropwise methanesulfonyl chloride (0.26 ml, 3.36 mmol) under argon at -20°C, and the mixture was stirred at -20°C for 1 h. The reaction mixture was diluted with dichloromethane and washed with water, 2 .0 M hydrochloric acid and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give a mixture of 4-[(4-bromothiophen-3-yloxy)methyl]benzylmethanesulfonate (0.94 g) as a light yellow oil. The resulting mixture of 4-[(4-bromothiophen-3-yloxy)methyl]benzylmethanesulfonate was used for the next reaction without purification.

¹ H-NMR(CDCl ₃ ) δ 7.41-7.53(4H, m), 7.21(1H, d, J=3.4 Hz), 6.28(1H, d, J=3, 5H), 5.25(2H, s), 5.11(2H, s), 2.94(3H, s).

[0251]

(42-4) Piperidine (0.27 ml, 2.73 mmol) and the mixture was stirred at 0°C for 20 min. A solution of a mixture of 4-[(4-bromothiophen-3-yloxy)methyl]benzylmethanesulfonate (0.94 g) in N,N-dimethylformamide (4 mL) was added dropwise to the suspension at 0°C, and the mixture was stirred at 0°C to room temperature for 18 hours. A saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrated residue was purified by column chromatography (dichloromethane/methanol) to give 1-{4-[(4-bromothiophen-3-yloxy)methyl]benzyl}piperidine (0.82 g, 2 steps, 99%) as a yellow oil.

¹ H-NMR(CDCl ₃ ) δ 7.30-7.42(4H, m), 7.19(1H, d, J=3.4 Hz), 6.28(1H, d, J=3, 5 Hz), 5.07(2H, s), 3.49(2H, s), 2.39(4H, br s), 1.53-1.63(4H, m), 1.38- 1.48(2H, m).

[0252]

(42-5) In a manner similar to that of Example 11, 3-(4-{4-[4-(piperidin-1-ylmethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazole was obtained -1-yl)piperidin-2,6-dione as a light brown amorphous substance (yield 10%) from 1-{4-[(4-bromothiophen-3-yloxy)methyl]benzyl}piperidine.

To a suspension of 3-(4-{4-[4-(piperidin-1-ylmethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidin-2,6-dione (212.9 mg, 0.46 mmol) in ethyl acetate (2 ml) was added 4.0 M hydrochloric acid/ethyl acetate solution (125.7 μl) at 0°C and the mixture was stirred at 0°C for 1 h. The precipitate was collected by filtration and the residue was recrystallized from ethyl acetate-methanol to give 3-(4-{4-[4-(piperidin-1-ylmethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazole hydrochloride -1-yl)piperidin-2,6-dione (133.0 mg, 57%) as a gray solid.

1-[4-({4-[(trimethylsilyl)ethynyl]thiophen-3-yloxy}methyl)benzyl]piperidine

¹ H-NMR(CDCl ₃ ) δ 7.28-7.45(5H, m), 6.23(1H, d, J=3.3 Hz), 5.07(2H, s), 3.48 (2H, s), 2.28-2.45(4H, br), 1.52-1.61(4H, m), 1.37-1.47(2H, m), 0.24( 9H, c).

1-{4-[(4-ethynylthiophen-3-yloxy)methyl]benzyl}piperidine

¹ H-NMR(CDCl ₃ ) δ 7.41(1H, d, J=3.3 Hz), 7.30-7.40(4H, m), 6.23(1H, d, J=3, 3 Hz), 5.08(2H, s), 3.47(2H, s), 3.17(1H, s), 2.27-2.46(4H, br), 1.52-1 .64(4H, m), 1.36-1.48(2H, m).

3-(4-{4-[4-(piperidin-1-ylmethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidin-2,6-dione hydrochloride

¹ H-NMR(DMSO-d ₆ ) δ 11.22(1H, br s), 10.52-10.70(1H, br), 8.32(1H, s), 7.88(1H , d, J=3.3 Hz), 7.54-7.66(4H, m), 6.84(1H, d, J=3.4 Hz), 5.89(1H, dd, J= 5.0, 12.4 Hz), 5.25(2H, s), 4.23(2H, d, J=5.3 Hz), 3.26(2H, broad d, J=11.8 Hz), 2.65-2.96(5H, m), 2.28-2.40(1H, m), 1.63-1.87(5H, m), 1.24-1.43( 1H, m).

[0253]

Example 43 (compound 43)

3-{4-[4-(4-chlorobenzyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione

(43-1) To a solution of methyl 4-bromo-3-hydroxythiophene-2-carboxylate (1.00 g, 4.22 mmol) in tetrahydrofuran (85 ml) was added p-chlorobenzyl alcohol (0.90 g, 6.31 mmol) and triphenylphosphine (2.21 g, 8.43 mmol), and diisopropyl azodicarboxylate (1.66 ml, 8.43 mmol) was added dropwise thereto at 0°C. Under argon atmosphere, the mixture was stirred at 0°C to room temperature for 17 hours. The reaction mixture was concentrated and the concentrated residue was purified by column chromatography (hexane/ethyl acetate) to give methyl 4-bromo-3-(4-chlorobenzyloxy)thiophene-2- carboxylate (1.48 g, 97%) as a white solid.

¹ H-NMR(CDCl ₃ ) δ 7.45-7.52(2H, m), 7.41(1H, s), 7.33-7.39(2H, m), 5.17(2H, c), 3.88(3H, s).

[0254]

(43-2) In a manner similar to that of Example 33 (33-2) and Example 38 (38-2), 3-bromo-4-(4-chlorobenzyloxy)thiophene was obtained as a white solid (97% yield) from methyl 4-bromo-3-(4-chlorobenzyloxy)thiophene-2-carboxylate.

4-bromo-3-(4-chlorobenzyloxy)thiophene-2-carboxylic acid

¹ H-NMR (CD ₃ OD) δ 7.68(1H, s), 7.48-7.54(2H, m), 7.33-7.40(2H, m), 5.18(2H , With).

3-bromo-4-(4-chlorobenzyloxy)thiophene

¹ H-NMR(CDCl ₃ ) δ 7.33-7.42(4H, m), 7.20(1H, d, J=3.5 Hz), 6.27(1H, d, J=3, 5 Hz), 5.05(2H, s).

[0255]

(43-3) In a manner similar to that of Example 11, 3-{4-[4-(4-chlorobenzyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidin- 2,6-dione as a white solid (19% yield) from 3-bromo-4-(4-chlorobenzyloxy)thiophene.

{[4-(4-chlorobenzyloxy)thiophen-3-yl]ethynyl}trimethylsilane

¹ H-NMR(CDCl ₃ ) δ 7.32-7.44(5H, m), 6.22(1H, d, J=3.3 Hz), 5.05(2H, s), 0.25 (9H, s).

3-(4-chlorobenzyloxy)-4-ethynylthiophene

¹ H-NMR(CDCl ₃ ) δ 7.42(1H, d, J=3.3 Hz), 7.32-7.41(4H, m), 6.21(1H, d, J=3, 3 Hz), 5.07(2H, s), 3.18(1H, s).

3-{4-[4-(4-chlorobenzyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione

¹ H-NMR(DMSO-d ₆ ) δ 11.23(1H, br s), 8.28(1H, s), 7.89(1H, d, J=3.4 Hz), 7.50 -7.55(2H, m), 7.44-7.49(2H, m), 6.82(1H, d, J=3.4Hz), 5.85(1H, dd, J=5 .2, 12.5 Hz), 5.21(2H, s), 2.64-2.93(3H, m), 2.28-2.40(1H, m).

[0256]

Example 44 (compound 44)

3-{4-[4-(1-phenylethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione

In a manner similar to that of Example 43, a mixture of optical isomers of 3-{4-[4-(1-phenylethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidin-2, 6-dione as a white solid (15% yield) from methyl 4-bromo-3-hydroxythiophene-2-carboxylate and (±)-1-phenylethyl alcohol.

methyl 4-bromo-3-(1-phenylethoxy)thiophene-2-carboxylate

¹ H-NMR(CDCl ₃ ) δ 7.43-7.50(2H, m), 7.33(1H, s), 7.24-7.38(3H, m), 5.75(1H, q, J=6.5 Hz), 3.83(3H, s), 1.68(3H, d, J=6.5 Hz).

4-bromo-3-(1-phenylethoxy)thiophene-2-carboxylic acid

¹ H-NMR(CDCl ₃ ) δ 7.45(1H, s), 7.42-7.47(2H, m), 7.28-7.38(3H, m), 5.85(1H, q, J=6.5 Hz), 1.73(3H, d, J=6.5 Hz).

3-bromo-4-(1-phenylethoxy)thiophene

¹ H-NMR(CDCl ₃ ) δ 7.32-7.41(4H, m), 7.24-7.30(1H, m), 7.12(1H, d, J=3.4 Hz) , 6.02(1H, d, J=3.5Hz), 5.18(1H, q, J=6.5Hz), 1.67(3H, d, J=6.4Hz).

trimethyl{[4-(1-phenylethoxy)thiophen-3-yl]ethynyl}silane

¹ H-NMR(CDCl ₃ ) δ 7.23-7.44(6H, m), 6.00(1H, d, J=3.3 Hz), 5.20(1H, q, J=6, 4 Hz), 1.65(3H, d, J=6.4 Hz), 0.27(9H, s).

3-ethynyl-4-(1-phenylethoxy)thiophene

¹ H-NMR(CDCl ₃ ) δ 7.24-7.41(6H, m), 5.98(1H, d, J=3.3 Hz), 5.20(1H, q, J=6, 5 Hz), 3.20(1H, s), 1.67(3H, d, J=6.5 Hz).

3-{4-[4-(1-phenylethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione

¹ H-NMR(DMSO-d ₆ ) δ 11.26(1H, s), 8.45(0.8H, s, large), 8.43(0.2H, s, small), 7.82( 1H, d, J=3.4 Hz), 7.43-7.48(2H, m), 7.31-7.38(2H, m), 7.23-7.30(1H, m) , 6.55(0.2H, d, J=3.4Hz, small), 6.52(0.8H, d, J=3.4Hz, large), 5.92(1H, dd, J =4.9, 12.2Hz), 5.46(1H, q, J=6.3Hz), 2.66-2.96(3H, m), 2.31-2.41(1H, m), 1.64(3H, d, J=6.4 Hz).

[0257]

Example 45 (compound 45)

3-(4-{4-[4-(2-morpholinoethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione hydrochloride

(45-1) In a manner similar to that of Example 43(43-1) and Example 33(33-2), 4-bromo-3-[4-(2-morpholinoethyl)benzyloxy]thiophene-2-carboxylic acid was obtained in as a white solid (86% yield) from methyl 4-bromo-3-hydroxythiophene-2-carboxylate and [4-(2-morpholinoethyl)phenyl]methanol.

methyl 4-bromo-3-[4-(2-morpholinoethyl)benzyloxy]thiophene-2-carboxylate

¹ H-NMR(CDCl ₃ ) δ 7.47(2H, d, J=8.1 Hz), 7.40(1H, s), 7.23(2H, d, J=8.1 Hz), 5.16(2H, s), 3.87(3H, s), 3.74(4H, t, J=4.7 Hz), 2.78-2.86(2H, m), 2.56 -2.63(2H, m), 2.46-2.56(4H, m).

4-bromo-3-[4-(2-morpholinoethyl)benzyloxy]thiophene-2-carboxylic acid

¹ H-NMR(DMSO-d ₆ ) δ 7.95(1H, s), 7.36-7.41(2H, m), 7.22-7.27(2H, m), 5.13( 2H, s), 3.54-3.63(4H, m), 2.72-2.80(2H, m), 2.43-2.59(6H, m).

[0258]

(45-2) Carbonate silver (24.0 mg, 0.09 mmol) and acetic acid (49 μl, 0.86 mmol) and the mixture was stirred at 120° C. for 15 minutes. Silver carbonate (48.6 mg, 0.18 mmol) was added in divided portions twice after 5 minutes and after 10 minutes. The reaction mixture was cooled to room temperature, 1.0 M hydrochloric acid and ethyl acetate were added, and the mixture was stirred for some time and neutralized with saturated aqueous sodium bicarbonate. The reaction mixture was filtered and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrated residue (266.1 mg) was dissolved in chloroform (2 ml), 4.0 M hydrochloric acid/ethyl acetate (0.3 ml, 1.2 mmol) was added followed by diethyl ether (2 ml) and the precipitate was collected filtration to give 4-{4-[(4-bromothiophen-3-yloxy)methyl]phenethyl}morpholine hydrochloride (278.4 mg, 85%) as a white solid.

¹ H-NMR(DMSO-d ₆ ) δ 10.73-10.96(1H, br.), 7.66(1H, d, J=3.5 Hz), 7.41-7.47(2H , m), 7.29-7.35(2H, m), 6.84(1H, d, J=3.5 Hz), 5.08(2H, s), 3.94-4.03( 2H, m), 3.77(2H, br. t, J=11.5 Hz), 3.44-3.53(2H, m), 3.28-3.38(2H, m), 3 .02-3.16(4H, m).

[0259]

(45-3) In a manner similar to that of Example 40 (40-2), 4-[4-({4-[(trimethylsilyl)ethynyl]thiophen-3-yloxy}methyl)phenethyl]morpholine (192.8 mg , 73%) as a red-brown oil from 4-{4-[(4-bromothiophen-3-yloxy)-methyl]-phenethyl}-morpholine hydrochloride (278.4 mg, 0.66 mol).

¹ H-NMR(CDCl ₃ ) δ 7.35-7.40(3H, m), 7.19-7.24(2H, m), 6.22(1H, d, J=3.3 Hz) , 5.06(2H, s), 3.72-3.77(4H, m), 2.78-2.85(2H, m), 2.48-2.63(6H, m), 0 .25(9H, s).

[0260]

(45-4) To a solution of 4-[4-({4-[(trimethylsilyl)ethynyl]thiophen-3-yloxy}methyl)phenethyl]morpholine (164.9 mg, 0.41 mmol) and acetic acid (0, 24 ml, 4.19 mmol) in tetrahydrofuran (1.7 ml) was added a 1 M solution of tetrabutylammonium/tetrahydrofuran (2.1 ml, 2.10 mmol) at 0°C and the mixture was stirred at 0°C to room temperature in for 6 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrated residue was purified by column chromatography (ethyl acetate/methanol) to give 4-{4-[(4-ethynylthiophen-3-yloxy)methyl]phenethyl}morpholine (116.1 mg, 85%) as a red-brown oil.

¹ H-NMR(CDCl ₃ ) δ 7.41(1H, d, J=3.4 Hz), 7.34-7.39(2H, m), 7.19-7.24(2H, m) , 6.22(1H, d, J=3.4 Hz), 5.07(2H, s), 3.75(4H, br. t, J=4.6 Hz), 3.17(1H, c), 2.77-2.87(2H, m), 2.49-2.65(6H, m).

[0261]

(45-5) To a suspension of 4-{4-[(4-ethynylthiophen-3-yloxy)methyl]phenethyl}morpholine (101.8 mg, 0.31 mmol) in tert-butyl alcohol (1.2 ml) and water (1.2 ml) was added 3-azidopiperidine-2,6-dione (synthesized by the method according to example 1 (1-1)) (53.2 mg, 0.35 mmol), copper (II) sulfate pentahydrate (7, 2 mg, 0.03 mmol) and sodium ascorbate (12.3 mg, 0.06 mmol), and the mixture was stirred under argon atmosphere at room temperature for 17 hours. Acetonitrile and methanol were added to the reaction mixture, and the insoluble material was dissolved, treated with activated charcoal and concentrated. The concentrated residue was purified by column chromatography (dichloromethane/methanol) and the resulting compound was dissolved in ethyl acetate (1.5 ml) and methanol (0.5 ml), and a 4.0 M hydrochloric acid/ethyl acetate solution (100 μl, 0.40 mmol) was added. ) was added at 0°C. Methanol was added to the reaction mixture, and the mixture was treated with activated carbon, and the solvent was evaporated. The precipitate was solidified in acetone to give 3-(4-{4-[4-(2-morpholinoethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidin-2 hydrochloride, 6-dione (39.8 mg, 26%) as a light brown solid.

¹ H-NMR(DMSO-d ₆ ) δ 11.24(1H, br s), 11.07-11.30(1H, br), 8.29(1H, s), 7.88(1H , d, J=3.3 Hz), 7.48(2H, d, J=8.1 Hz), 7.30(2H, d, J=8.1 Hz), 6.81(1H, d , J=3.4 Hz), 5.88(1H, dd, J=5.0, 12.3 Hz), 5.20(2H, s), 3.98(2H, broad dd, J= 2.3, 12.3 Hz), 3.80(2H, br. t, J=11.5 Hz), 3.47(2H, br. d, J=12.3 Hz), 3.25- 3.37(2H, m), 2.99-3.15(4H, m), 2.63-2.95(3H, m), 2.28-2.39(1H, m).

[0262]

Example 46 (compound 46)

3-[4-(4-{4-[(dimethylamino)methyl]benzyloxy}thiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione hydrochloride

(46-1) In a manner similar to that of Example 36 (36-4), [4-({4-[(trimethylsilyl)ethynyl]thiophen-3-yloxy}methyl)phenyl]methanol (468.5 mg, 59 %) as a red-brown oil from {4-[(4-bromothiophen-3-yloxy)methyl]phenyl}methanol (synthesized according to the method according to example 42 (42-1, 42-2)) (754.3 mg, 2 .52 mmol).

¹ H-NMR(CDCl ₃ ) δ 7.33-7.52(5H, m), 6.22(1H, d, J=3.3 Hz), 5.09(2H, s), 4.71 (2H, d, J=5.9 Hz), 1.65(1H, br. t, J=6.0 Hz), 0.25(9H, s).

[0263]

(46-2) To a solution of [4-({4-[(trimethylsilyl)ethynyl]thiophen-3-yloxy}methyl)phenyl]methanol (468.5 mg, 1.48 mmol) in dichloromethane (5.9 ml) triethylamine (0.41 ml, 2.94 mmol) and methanesulfonyl chloride (0.17 ml, 2.20 mmol) were added at -20°C and the mixture was stirred at -20°C to -9°C for 1 h The reaction mixture was diluted with dichloromethane, washed with 1.0 M hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrated residue (624.1 mg) was dissolved in dichloromethane (15 ml), a 2 M dimethylamine/methanol solution (2.2 ml, 4.4 mmol) was added at 0°C and the mixture was stirred at 0°C to room temperature for 17.5 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrated residue was purified by column chromatography (dichloromethane/methanol) to obtain a mixture of 1-[4-({[4-(trimethylsilyl)ethynyl]thiophen-3-yloxy}methyl)phenyl]-N,N-dimethylmethanamine (373.7 mg) as brown oil. To a solution of the resulting mixture (373.7 mg) in methanol (2.2 ml) was added potassium carbonate (303.9 mg, 2.20 mmol) and the mixture was stirred at room temperature for 25 hours. Saturated brine was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrated residue was purified by column chromatography (dichloromethane/methanol) to give 1-{4-[(4-ethynylthiophen-3-yloxy)methyl]phenyl}-N,N-dimethylmethanamine (175.7 mg, 44%) as red brown oil.

¹ H-NMR(CDCl ₃ ) δ 7.38-7.43(3H, m), 7.29-7.35(2H, m), 6.22(1H, d, J=3.3 Hz) , 5.09(2H, s), 3.43(2H, s), 3.17(1H, s), 2.24(6H, s).

[0264]

(46-3) In a manner similar to that of Example 1 (1-2), 3-[4-(4-{4-[(dimethylamino)methyl]benzyloxy}thiophen-3-yl)-1H-1,2 was obtained ,3-triazol-1-yl]piperidin-2,6-dione (227.5 mg) as green oil from 1-{4-[(4-ethynylthiophen-3-yloxy)methyl]phenyl}-N,N -dimethylmethanamine (175.7 mg, 0.65 mmol).

The resulting green oil (227.5 mg) was dissolved in ethyl acetate (2 ml) and methanol (2 ml), and a 4.0 M hydrochloric acid/ethyl acetate solution (0.3 ml, 1.20 mmol) was added at room temperature. The solvent was evaporated and the residue was dissolved in methanol and treated with activated charcoal. The solvent was evaporated and the resulting residue was suspended in methanol (0.5 ml). Insoluble material was removed by filtration and the filtrate was concentrated. The concentrated residue was dissolved in methanol (0.3 ml) at 40°C and left to stand at 5°C to ensure the precipitation of a solid. Methanol (1.0 ml) was added and the precipitate was collected by filtration and washed with methanol, ethyl acetate and diethyl ether to give 3-[4-(4-{4-[(dimethylamino)methyl]benzyloxy}thiophen-3-yl)- hydrochloride 1H-1,2,3-triazol-1-yl]piperidin-2,6-dione (87.6 mg, 29%) as a white solid.

¹ H-NMR(DMSO-d ₆ ) δ 11.23(1H, br s), 10.07-10.60(1H, br), 8.32(1H, s), 7.88(1H , d, J=3.4 Hz), 7.52-7.62(4H, m), 6.82(1H, d, J=3.4 Hz), 5.88(1H, dd, J= 5.0, 12.4 Hz), 5.26(2H, s), 4.26(2H, br s), 2.59-2.95(9H, m), 2.28-2.40 (1H, m).

[0265]

Example 47 (compound 47)

3-{4-[4-(benzo[b]thiophen-2-ylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione

(47-1) In a manner similar to that of Example 43 (43-1), methyl 3-(benzo[b]thiophen-2-ylmethoxy)-4-bromothiophene-2-carboxylate (1.20 g, 93%) was obtained as a white solid from benzo[b]thiophene-2-methanol (0.72 g, 4.38 mmol) and methyl 4-bromo-3-hydroxythiophene-2-carboxylate (0.80 g, 3.37 mmol) .

¹ H-NMR(CDCl ₃ ) δ 7.80-7.86(1H, m), 7.73-7.79(1H, m), 7.41(1H, s), 7.37(1H, brd, J=0.7 Hz), 7.31-7.38(2H, m), 5.49(2H, d, J=0.7 Hz), 3.90(3H, s).

[0266]

(47-2) Methyl 3-(benzo[b]thiophen-2-ylmethoxy)-4-bromothiophene-2-carboxylate (1.17 g, 3.05 mmol) was dissolved in a mixed solution of tetrahydrofuran (70 ml)-water ( 9.4 ml), 1.25 M aqueous lithium hydroxide solution (18.8 ml, 23.5 mmol) was added at 0°C and the mixture was stirred at 0°C to room temperature for 17 h. The reaction mixture was concentrated , 1.0 M hydrochloric acid (25 ml, 25 mmol) was added and the precipitate was collected by filtration to give 3-(benzo[b]thiophen-2-ylmethoxy)-4-bromothiophene-2-carboxylic acid (1.10 g, 98 %) as a white solid.

¹ H-NMR(DMSO-d ₆ ) δ 7.90-8.00(2H, m), 7.81-7.88(1H, m), 7.47(1H, s), 7.32- 7.42(2H, m), 5.53(2H, s).

[0267]

(47-3) In a manner similar to that of Example 38 (38-2) and Example 40 (40-2, 40-3), 3-{4-[4-(benzo[b]thiophen-2-ylmethoxy) was obtained thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidin-2,6-dione as white solid (14% yield) from 3-(benzo[b]thiophene-2- ylmethoxy)-4-bromothiophene-2-carboxylic acid.

2-[(4-bromothiophen-3-yloxy)methyl]benzo[b]thiophene

¹ H-NMR(CDCl ₃ ) δ 7.79-7.86(1H, m), 7.72-7.79(1H, m), 7.29-7.39(3H, m), 7, 20(1H, d, J=3.5 Hz), 6.39(1H, d, J=3.5 Hz), 5.34(2H, d, J=0.8 Hz).

2-[(4-ethynylthiophen-3-yloxy)methyl]benzo[b]thiophene

¹ H-NMR(CDCl ₃ ) δ 7.79-7.84(1H, m), 7.73-7.77(1H, m), 7.42(1H, d, J=3.3 Hz) , 7.29-7.39(3H, m), 6.34(1H, d, J=3.3 Hz), 5.35(2H, d, J=0.9 Hz), 3.19( 1H, s).

3-{4-[4-(benzo[b]thiophen-2-ylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione

¹ H-NMR(DMSO-d ₆ ) δ 11.11-11.30(1H, br s), 8.28(1H, s), 7.93-7.98(1H, m), 7, 91 (1H, d, J=3.4 Hz), 7.82-7.88(1H, m), 7.58(1H, d, J=0.3 Hz), 7.33-7.41 (2H, m), 6.96(1H, d, J=3.4Hz), 5.86(1H, dd, J=5.0, 12.4Hz), 5.52(2H, s) , 2.64-2.91(3H, m), 2.29-2.40(1H, m).

[0268]

Example 48 (compound 48)

3-[5-bromo-4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

To a suspension of N-bromosuccinimide (1.19 g, 6.69 mmol) and silver nitrate (107.2 mg, 0.63 mmol) in acetone (30 ml) was added 3-ethynylthiophene (0.60 ml, 6.03 mmol ), and the mixture was stirred in the dark at room temperature for 16.5 hours. The reaction mixture was diluted with hexane and washed with saturated brine and 1.0 M aqueous sodium thiosulfate. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give a mixture of 3-(bromoethynyl)thiophene (1.21 g) as a brown oil. The resulting mixture (1.21 g) was dissolved in tetrahydrofuran (12 ml), 3-azidopiperidine-2,6-dione (synthesized by the method according to Example 1 (1-1)) (0.97 g, 6.29 mmol) was added, copper(II) acetate (53.6 mg, 0.30 mmol) and copper(I) iodide (56.1 mg, 0.29 mmol) and the mixture was stirred under argon at 50° C. for 2 days. Water (12 ml) was added to the reaction mixture, and the precipitate was collected by filtration and washed with water and acetonitrile. The residue was recrystallized from dimethylsulfoxide-water to give 3-[5-bromo-4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione (1, 14 g, 55%) as a gray solid.

¹ H-NMR(DMSO-d ₆ ) δ 11.33(1H, br s), 8.04(1H, dd, J=1.3, 2.9 Hz), 7.75(1H, dd, J=2.9, 5.0Hz), 7.66(1H, dd, J=1.3, 5.0Hz), 5.86(1H, dd, J=5.1, 12.6Hz ), 2.96(1H, ddd, J=5.1, 13.1, 16.6 Hz), 2.83(1H, dq, J=4.2, 12.7 Hz), 2.65- 2.77(1H, m), 2.37-2.46(1H, m).

[0269]

Example 49 (compound 49)

3-[5-iodo-4-(4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

(49-1) N-iodomorpholine hydroiodide (420.2 mg , 1.23 mmol) and copper(I) iodide (10.2 mg, 0.05 mmol), and the mixture was stirred at room temperature for 26.5 hours. Hexane was added to the reaction mixture and the mixture was washed with saturated brine and 1. 0 M aqueous sodium thiosulfate solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give 3-(iodoethynyl)-4-methoxythiophene (232.2 mg, 89%) as a red-brown oil.

¹ H-NMR(CDCl ₃ ) δ 7.38(1H, d, J=3.3 Hz), 6.19(1H, d, J=3.3 Hz), 3.86(3H, s).

[0270]

(49-2) To a solution of 3-(iodoethynyl)-4-methoxythiophene (232.2 mg, 0.88 mmol) in tetrahydrofuran (1.8 ml) was added 3-azidopiperidine-2,6-dione , 0.94 mmol), tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (25.4 mg, 0.05 mmol) and copper(I) iodide (9 .2 mg, 0.05 mmol) and the mixture was stirred at room temperature for 4 days. The reaction mixture was concentrated and the concentrated residue was purified by column chromatography (hexane/ethyl acetate) to give a light green solid (287.0 mg). The resulting light green solid was washed with methanol and ethyl acetate and then with chloroform and methanol, and dissolved in dimethyl sulfoxide (1 ml). Water (0.8 ml) was added and the precipitate was collected by filtration. The residue was washed with methanol and ethyl acetate to give 3-[5-iodo-4-(4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione (157, 5 mg, 43%) as a white solid.

¹ H-NMR(DMSO-d ₆ ) δ 11.15-11.42(1H, br s), 7.66(1H, d, J=3.3 Hz), 6.75(1H, d, J=3.3Hz), 5.77(1H, dd, J=5.1, 12.4Hz), 3.78(3H, s), 2.98(1H, dd, J=5.3 , 12.9, 16.8 Hz), 2.74-2.88(1H, m), 2.70(1H, ddd, J=2.8, 4.0, 16.8 Hz), 2, 30-2.43(1H, m).

[0271]

Example 50 Human TNF-α production suppression test

Healthy adult peripheral blood was collected in a vacuum blood collection tube (Terumo containing EDTA/2Na) and then diluted two times with an equal volume of OTSUKA NORMAL SALINE (Otsuka Pharmaceutical Co., Ltd.). The diluted blood was mixed with Lymphoprep (AXIS-SHIELD) at half the volume of the diluted blood, transferred to a 15 ml conical tube and centrifuged at room temperature for 20 min (2100 rpm). Mononuclear cells accumulated at the contact surface between Lymphoprep and plasma were transferred to a 50 ml conical tube, diluted with OTSUKA NORMAL SALINE, and the mononuclear cell suspension was centrifuged at room temperature for 10 min (1150 rpm), and then the supernatant was removed . The mononuclear cell fraction obtained as precipitate was suspended in an appropriate amount of 10% fetal bovine serum (Thermo Fisher Scientific)-containing RPMI1640 medium (Thermo Fisher Scientific, hereinafter abbreviated as medium A), and diluted appropriately with 0.4% trypanic acid solution. blue (Sigma-Aldrich Co. LLC.). The number of viable cells was counted using a hemocytometer (ERMA INC.). They were diluted with medium A to give a value of 5×10 ⁵ cells/ml. On the other hand, 75 µl of medium A, 5 µl of test compound solution at a concentration of 0.4 mg/ml (solution in DMSO diluted in 10 medium A), and 20 µl of lipopolysaccharide solution at a concentration of 10 µg/ml (Sigma-Aldrich Co. LLC.) (diluted with medium A) was added in advance to the same well of a 96-well Falcon flat bottom plate (Corning Incorporated) in each case, and the above cell suspension was dispensed in an amount of 0.1 ml/well. Instead of the compound solution, 5 μl of DMSO diluted 10 times with medium A was added to the control well. After cultivation at 37°C in a flow of 5% CO ₂ for 24 h, the culture solution was centrifuged at 4°C, 1000 rpm, for 3 min and the supernatant was collected. The content of TNF-α in the supernatant was determined using an ELISA kit (Peprotech) in accordance with the conventional method. The amount of TNF-α produced in the well containing the test compound was determined by taking the amount of TNF-α produced in the control well as 100, and the rate of suppression was calculated for each test. As shown in Table 1, the compound of the present invention exhibited a marked TNF-α production suppression activity at a concentration of 10 μg/ml.

[0272]

[Table 1]

Table 1 TNF-α production suppression rate (%)

compound 1 90 compound 18 100 compound 35 70 compound 2 98 compound 19 83 compound 36 98 compound 3 59 compound 20 87 compound 37 81 compound 4 67 connection 21 thirty connection 38 89 connection 5 71 connection 22 48 connection 39 81 compound 6 67 connection 23 62 connection 40 86 connection 7 73 connection 24 75 compound 41 93 connection 8 64 connection 25 49 connection 42 96 compound 9 41 compound 26 83 connection 43 87 connection 10 fifty connection 27 39 connection 44 79 connection 11 81 connection 28 37 connection 45 76 compound 12 84 connection 29 57 connection 46 80 compound 13 35 compound 30 79 connection 47 63 compound 14 75 connection 31' 82 connection 48 51 connection 15 85 connection 32 100 connection 49 79 connection 16 100 compound 33 100 - - connection 17 92 connection 34 97 - -

(' suppression level at 3 µg/mL)

[0273]

Example 51 Proliferation Suppression Assay for Human Myeloma Cell Line MM.1S

MM.1S cells (ATCC, CRL-2974) were suspended in RPMI1640 medium (ATCC, hereinafter abbreviated as medium B) containing 10% fetal calf serum (Thermo Fisher Scientific) and diluted appropriately with 0.4% trypan blue solution ( Sigma-Aldrich Co. LLC.). The number of viable cells was counted using a hemocytometer (ERMA INC.). They were diluted with medium B so that the final value was 2×10 ⁵ cells/ml. On the other hand, 50 μl of a solution prepared by diluting a 4 mM DMSO solution of the test compound 200-fold with medium B was added to each well of a 96-well Falcon flat bottom plate (Corning Incorporated), and the above cell suspension was dispensed in an amount of 50 μl/ well (final concentration of test compound 10 µm). 50 µl of a solution obtained by diluting DMSO 200 times with medium B was added to the control well. After cultivation at 37°C in a flow of 5% CO ₂ for 3 days, cell proliferation activity was determined using the WST-1 kit (DOJINDO LABORATORIES) or the WST kit -8 Kit (KISHIDA CHEMICAL Co., Ltd.) and according to the instructions included with each one. As shown in Table 2, the compound of the present invention exhibited remarkable activity of suppressing the proliferation of MM.1S cells.

[0274]

Example 52 Proliferation Suppression Test for Diffuse Human Large B-cell Lymphoma Cell Line Pfeiffer

Pfeiffer cells (ATCC, CRL-2632) were suspended in medium B and diluted appropriately with 0.4% trypan blue solution (Sigma-Aldrich Co. LLC.). The number of viable cells was counted using a hemocytometer (Funakoshi Co., Ltd.). The cell suspension obtained by diluting medium B to 1.3×10 ⁵ cells/ml was dispensed into a 96-well Falcon flat bottom plate (Corning Incorporated) at 75 μl/well and culture started at 37° C. in flow 5 %CO2 _. The next day, a solution prepared by diluting a 4 mM solution of the test compound in DMSO 100 times with medium B was added to each well, 25 μl (final concentration of the test compound 10 μm). 25 μl _of a solution obtained by diluting 100 times with DMSO with medium B was added to the control well. transferred to another new 96-well flat bottom Falcon plate. A solution obtained by diluting a 4 mM DMSO solution of the same test compound as the first time by 400 times with medium B was added 86 µl to a total of 100 µl (final concentration of test compound 10 µM). After culturing at 37° C. in a 5% CO ₂ flow for 3 days, cell proliferation activities were determined according to the instructions supplied with the WST-8 Kit (KISHIDA CHEMICAL Co., Ltd.). As shown in Table 2, the compound of the present invention showed a remarkable activity of suppressing the proliferation of Pfeiffer cells.

[0275]

Example 53 Proliferation Suppression Assay for Human Mantle Cell Lymphoma Cell Line REC-1

REC-1 cells (ATCC, CRL-3004) were suspended in medium B and diluted appropriately with 0.4% trypan blue solution (Sigma-Aldrich Co. LLC.). The number of viable cells was counted using a hemocytometer (Funakoshi Co., Ltd.). The cell suspension obtained by diluting medium B to 1.3×10 ⁵ cells/ml was dispensed into a 96-well Falcon flat bottom plate (Corning Incorporated) at 75 μl/well and culture started at 37° C. in flow 5 %CO2 _. The next day, a solution prepared by diluting a 4 mM solution of the test compound in DMSO 100 times with medium B was added to each well, 25 μl (final concentration of the test compound 10 μm). 25 µl of a solution obtained by diluting DMSO 100 times with medium B was added to the control well. After culturing at 37°C in a flow of 5% CO ₂ for 3 days, cell proliferation activities were determined according to the instructions supplied with the WST-8 Kit. (KISHIDA CHEMICAL Co., Ltd.). As shown in Table 2, the compound of the present invention showed a marked activity of suppressing the proliferation of REC-1 cells.

[0276]

Example 54 Daudi human Burkitt lymphoma cell proliferation suppression test

Daudi cells (National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), JCRB9071) were suspended in medium B and diluted appropriately with 0.4% trypan blue solution (Sigma-Aldrich Co. LLC.). The number of viable cells was counted using a hemocytometer (ERMA INC.). The cell suspension obtained by diluting medium B to 1.3×10 ⁵ cells/ml was dispensed into a 96-well Falcon flat bottom plate (Corning Incorporated) at 75 μl/well and culture started at 37° C. in flow 5 %CO2 _. The next day, a solution prepared by diluting a 4 mM solution of the test compound in DMSO 100 times with medium B was added to each well, 25 μl (final concentration of the test compound 10 μm). 25 µl of a solution obtained by diluting DMSO 100 times with medium B was added to the control well. After culturing at 37°C in a flow of 5% CO ₂ for 3 days, cell proliferation activities were determined according to the instructions supplied with the WST-8 Kit. (KISHIDA CHEMICAL Co., Ltd.). As shown in Table 2, the compound of the present invention exhibited remarkable activity of inhibiting Daudi cell proliferation.

[0277]

Example 55 Proliferation Suppression Assay for Acute Lymphoblastic Leukemia Cell Line Kasumi-7

Kasumi-7 cells (NIBIOHN, JCRB1401) were suspended in RPMI1640 medium (ATCC, hereinafter abbreviated as medium C) containing 20% fetal calf serum (Thermo Fisher Scientific) and diluted appropriately with 0.4% trypan blue solution (Sigma- Aldrich Co. LLC.). The number of viable cells was counted using a hemocytometer (Funakoshi Co., Ltd.). The cell suspension prepared by diluting medium C to 1.3×10 ⁵ cells/mL was dispensed into a 96-well Falcon flat bottom plate (Corning Incorporated) at 75 μl/well and culture started at 37° C. in flow 5 %CO2 _. The next day, a solution prepared by diluting a 4 mM solution of the test compound in DMSO 100 times with medium C, 25 μl (final concentration of the test compound 10 μm) was added to each well. 25 μl of a solution obtained by diluting DMSO 100 times with medium C was added to the control well. After cultivation at 37°C in a flow of 5% CO ₂ for 3 days, cell proliferation activities were determined according to the instructions supplied with the WST-8 Kit. (KISHIDA CHEMICAL Co., Ltd.). As shown in Table 2, the compound of the present invention showed remarkable activity of suppressing the proliferation of Kasumi-7 cells.

[0278]

Example 56 Cytotoxicity Test Using Human Peripheral Blood Mononuclear Cells (PBMC)

Healthy adult peripheral blood was collected in a Venoject II vacuum blood collection tube (Terumo containing EDTA/2Na) and then diluted two-fold with an equal volume of OTSUKA NORMAL SALINE (Otsuka Pharmaceutical Co., Ltd.). The diluted blood was mixed with Lymphoprep (AXIS-SHIELD) at half the volume of the diluted blood, transferred to a 15 ml conical tube and centrifuged at room temperature for 20 min (2100 rpm). Mononuclear cells accumulated at the contact surface between Lymphoprep and plasma were transferred to a 50 ml conical tube, diluted with OTSUKA NORMAL SALINE, and the mononuclear cell suspension was centrifuged at room temperature for 10 min (1150 rpm), and then the supernatant was removed . The mononuclear cell fraction obtained as a precipitate was suspended in an appropriate amount of medium A and diluted appropriately with a 0.4% trypan blue solution (Sigma-Aldrich Co. LLC.). The number of viable cells was counted using a hemocytometer (ERMA INC.). They were diluted with medium A so that the resulting value was 5×10 ⁵ cells/ml. On the other hand, 37.5 µl of medium A, 2.5 µl of test compound solution at a concentration of 0.4 mg/ml (solution in DMSO diluted in 10 medium A), and 10 µl of lipopolysaccharide solution at a concentration of 10 µg/ml (Sigma -Aldrich Co. LLC.) (diluted with medium A) was added in advance to the same well of a 96-well Falcon flat bottom plate (Corning Incorporated) in each case, and the above cell suspension was dispensed in an amount of 50 μl/well (final concentration of test compounds 10 μg/ml). 2.5 µl _of DMSO diluted 10 times with medium A was added to the control well instead of the compound solution. WST-8 kit (KISHIDA CHEMICAL Co., Ltd.) according to the instructions included with each. As shown in Table 2, the compound of the present invention did not show significant cytotoxicity.

[0279]

[Table 2]

Table 2 Cell proliferation inhibition activity

compound
(10 µm) cell survival (% of control) cell survival
(% of control) MM.1S Pfeiffer REC-1 Daudi Kasumi-7 PBMC* one 33 89 43 61 65 106 2 fifty 80 36 71 68 100 3 59 96 65 78 81 89 four 87 98 93 82 91 112 5 66 98 53 82 72 97 6 63 100 52 79 72 96 7 57 101 44 75 69 101 eight 94 107 99 93 94 97 9 77 100 70 83 90 129 ten 78 113 57 85 72 97 eleven 63 114 56 94 78 115 12 74 94 77 87 89 101 13 79 100 100 95 93 132 fourteen 43 74 34 49 64 113 fifteen 55 87 36 61 60 105 16 85 98 85 83 90 90 17 32 72 23 fifty 48 49 eighteen 27 70 eighteen 51 52 53 19 24 eleven four four 24 99 twenty 35 81 22 55 53 104 21 75 106 63 86 79 116 22 73 97 65 81 82 132 23 75 97 70 76 76 104 24 63 91 46 69 72 91 25 69 84 57 68 73 118 26 40 82 23 51 fifty 42 27 82 98 80 70 83 107 28 68 91 58 78 75 89 29 89 110 86 79 84 104 thirty 59 99 49 76 62 70 31 27 82 27 39 43 106** 32 27 60 fifteen 23 36 66 33 49 71 27 27 38 78 34 fifty 104 33 48 45 95 35 55 104 39 67 53 100 36 16 34 2 6 19 59 37 24 71 17 twenty 38 99 38 24 29 5 7 23 110 39 26 69 24 thirty 36 98 40 35 91 33 46 41 96 41 32 72 twenty 24 26 110 42 27 63 13 17 26 103 43 thirty 89 23 36 42 98 44 33 94 thirty 41 40 105 45 31 78 26 40 39 110 46 35 84 23 29 35 110 47 64 99 33 87 56 106 48 85 98 98 80 95 138 49 48 75 24 42 56 102 Thalidomide 79 104 94 81 96 -

* PBMC survival was determined at a compound concentration of 10 µg/mL

** Changed to 3 µg/mL due to precipitation of the compound in the medium

⃰ -: no data

[Industrial applicability]

[0280]

The present invention relates to novel thiophene derivatives having a TNF-α production suppression activity and a hematological cell proliferation inhibiting activity, and is useful for treating rheumatoid arthritis, Crohn's disease, ulcerative colitis, and moreover, hematological malignancy, and a drug containing them. The present invention is useful in the field of pharmaceutical products.

[0281]

This application is based on Patent Application No. 2018-010984 filed in Japan (Filed Date: January 25, 2018) and Patent Application No. 2018-084202 filed in Japan (Filed Date: April 25, 2018), the contents of which are covered by the present description in in full.

Claims (188)

1. A compound corresponding to the following general formula (I):

where: R ₁ is hydrogen or halogen; R of m is independently in each occurrence halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 chain alkoxy, C3-6 cycloalkoxy, or alkoxy corresponding to the formula -O-X-Y, where: X is a linear or branched C1-6 alkylene; and Y is C3-6 cycloalkyl, pyridine or benzothiophene, or a substituent corresponding to the general formula (II):

Z represents hydrogen, C1-6 alkoxy, C1-6 alkoxymethyl, halogen, or a substituent corresponding to the following general formulas (III), (IV), (V) or (VI):

Z ₁ and Z ₂ are each independently hydrogen or C1-6 alkyl, or Z ₁ and Z ₂ are connected to each other to form, together with the nitrogen atom to which they are attached, a 5- or 6-membered ring; and n is 1 or 2;

; or C1-6 alkoxycarbonyl or C1-6 alkylcarbonyl, or two Rs on adjacent ring carbons are bonded to each other to form, together with the carbons to which they are attached, a 5- or 6-membered ring containing 1-2 oxygen atoms; and m is 0, 1, 2 or 3, or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound corresponding to the general formula (I) is a compound corresponding to the following general formula (IA) or (IB):

where: R ₁ is hydrogen or halogen; R ₂ is hydrogen, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, or C1-6 alkylcarbonyl; R ₃ is hydrogen, halogen, C1-6 alkyl, or C1-6 chain alkoxy, C3-6 cycloalkoxy, or alkoxy corresponding to the formula -OX—Y, where: X is a linear or branched C1-6 alkylene; and Y is C3-6 cycloalkyl or pyridine or benzothiophene, each of which optionally has a substituent or substituent corresponding to the general formula (II):

Z represents hydrogen, C1-6 alkoxy, C1-6 alkoxymethyl, halogen, or a substituent corresponding to the following general formulas (III), (IV), (V) or (VI):

Z ₁ and Z ₂ are each independently hydrogen or C1-6 alkyl, or Z ₁ and Z ₂ are connected to each other to form, together with the nitrogen atom to which they are attached, a 5- or 6-membered ring; and n is 1 or 2;

; R ₄ is hydrogen, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, or C1-6 alkylcarbonyl; R ₅ is hydrogen, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, or C1-6 alkylcarbonyl; R ₆ is hydrogen, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, or C1-6 alkylcarbonyl, or R ₅ and R ₆ are connected to each other to form, together with the carbon atoms to which they are attached, a 5- or 6-membered ring containing 1-2 oxygen atoms; and R ₇ is hydrogen, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, or C1-6 alkylcarbonyl. 3. The compound according to claim 2 or its pharmaceutically acceptable salt, where R ₁ represents hydrogen or halogen; R ₂ is hydrogen, halogen or C1-6 alkoxy; R ₃ is hydrogen, halogen, C1-6 alkyl or alkoxy with C1-6 chain, C3-6 cycloalkoxy, or alkoxy corresponding to the formula -OX—Y, where: X is a linear or branched C1-6 alkylene; and Y is C3-6 cycloalkyl or pyridine or benzothiophene, each of which optionally has a substituent, or substituent corresponding to the general formula (II)

Z represents hydrogen, C1-6 alkoxy, C1-6 alkoxymethyl, halogen, or a substituent corresponding to the following general formulas (III), (IV), (V) or (VI):

Z ₁ and Z ₂ are each independently hydrogen or C1-6 alkyl, or Z ₁ and Z ₂ are connected to each other to form, together with the nitrogen atom to which they are attached, a 5- or 6-membered ring; and n is 1 or 2;

; R ₄ is hydrogen, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, or C1-6 alkoxycarbonyl; each of R ₅ and R ₆ is hydrogen, or R ₅ and R ₆ are connected to each other to form, together with the carbon atoms to which they are attached, a 5- or 6-membered ring containing 1-2 oxygen atoms; and R ₇ is hydrogen, halogen, C1-6 alkyl or C1-6 alkylcarbonyl. 4. A compound according to claim 1 wherein X is CH ₂ , CH(CH ₃ ) or CH ₂ CH ₂ , or a pharmaceutically acceptable salt thereof. 5. The compound according to any one of paragraphs.2-4 or its pharmaceutically acceptable salt, where R ₁ represents hydrogen, iodine, bromine or chlorine; R ₂ represents hydrogen, bromine or methoxy; R ₃ is hydrogen, bromine, chlorine, methyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, cyclopentyloxy, cyclopropylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, benzyloxy, 1-phenylethoxy, pyridin-2-ylmethoxy, pyridin-3-ylmethoxy, pyridine- 4-ylmethoxy, benzo[b]thiophen-2-ylmethoxy, 4-methoxybenzyloxy, 4-(methoxymethyl)benzyloxy, 4-chlorobenzyloxy, 4-(pyrrolidin-1-ylmethyl)benzyloxy, 4-(piperidin-1-ylmethyl)benzyloxy , 4-[(dimethylamino)methyl]benzyloxy, 4-(2-morpholinoethyl)benzyloxy, 2-(morpholinomethyl)benzyloxy, 3-(morpholinomethyl)benzyloxy, 4-(morpholinomethyl)benzyloxy or 4-{[(2S,6R) -2,6-dimethylmorpholino]methyl}benzyloxy; R ₄ is hydrogen, bromine, chlorine, methyl, hydroxymethyl, methoxy, ethoxy or methoxycarbonyl; each of R ₅ and R ₆ is hydrogen, or R ₅ and R ₆ are connected to each other to form, together with the carbon atoms to which they are attached, a 6-membered ring containing two oxygen atoms; R ₇ represents hydrogen, chlorine, bromine, methyl or acetyl. 6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound or salt is selected from the following: 3-[4-(4-bromothiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione, 3-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione, 3-[4-(thiophen-2-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione, 3-[5-chloro-4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione, 3-[4-(5-methylthiophen-2-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione, 3-[4-(5-methylthiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione, 3-[4-(4-methylthiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione, 3-[4-(5-acetylthiophen-2-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione, 3-{4-[5-(hydroxymethyl)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidin-2,6-dione, 3-[4-(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6- dion, 3-[4-(5-chlorothiophen-2-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione, 3-[4-(5-bromothiophen-2-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione, 3-[4-(2,5-dibromothiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione, 3-[4-(4-chlorothiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione, 3-[4-(4-Methoxy-5-methylthiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione, methyl 4-[1-(2,6-dioxopiperidin-3-yl)-1H-1,2,3-triazol-4-yl]-3-methoxythiophene-2-carboxylate, 3-[4-(4-ethoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione, 3-[4-(2-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione, 3-[4-(4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione, 3-[4-(5-Methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione, 3-[4-(4-propoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione, 3-[4-(5-chloro-4-methoxythiophene) -3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione, 3-[4-(5-bromo-4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione, 3-[4-(5-ethoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione, 3-[4-(4-butoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione, 3-[4-(4-isopropoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione, 3-{4-[4-(cyclopentyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidin-2,6-dione, 3-{4-[4-(cyclopropylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidin-2,6-dione, 3-{4-[4-(cyclopentylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione, 3-{4-[4-(cyclohexylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione, 3-{4-[4-(4-methoxybenzyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione, 3-{4-[4-(benzyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidin-2,6-dione, 3-{4-[4-(pyridin-4-ylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione, 3-{4-[4-(pyridin-2-ylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione, 3-{4-[4-(pyridin-3-ylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione, 3-(4-{4-[4-(morpholinomethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione, 3-(4-{4-[4-(methoxymethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione, 3-{4-[4-(4-{[(2S,6R)-2,6-dimethylmorpholino]methyl}benzyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl} piperidine-2,6-dione, 3-(4-{4-[3-(morpholinomethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione, 3-(4-{4-[2-(morpholinomethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione, 3-(4-{4-[4-(pyrrolidin-1-ylmethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidin-2,6-dione, 3-(4-{4-[4-(piperidin-1-ylmethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidin-2,6-dione, 3-{4-[4-(4-chlorobenzyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione, 3-{4-[4-(1-phenylethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione, 3-(4-{4-[4-(2-morpholinoethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione, 3-[4-(4-{4-[(dimethylamino)methyl]benzyloxy}thiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione, 3-{4-[4-(benzo[b]thiophen-2-ylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidin-2,6-dione, 3-[5-bromo-4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione, and 3-[5-iodo-4-(4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione. 7. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound corresponding to the general formula (I) is a compound corresponding to the following general formula (IA):

where: R ₁ is hydrogen; R ₂ is hydrogen; R ₃ is hydrogen or alkoxy chain C1-6, C3-6 cycloalkoxy, or alkoxy corresponding to the formula -O-X-Y, where: X is a linear or branched C1-6 alkylene; and Y is C3-6 cycloalkyl or pyridine or benzothiophene, each of which optionally has a substituent or substituent corresponding to the general formula (II):

Z represents hydrogen, C1-6 alkoxy, C1-6 alkoxymethyl, halogen, or a substituent corresponding to the following general formulas (III), (IV), (V) or (VI):

Z ₁ and Z ₂ are each independently hydrogen or C1-6 alkyl, or Z ₁ and Z ₂ are connected to each other to form, together with the nitrogen atom to which they are attached, a 5- or 6-membered ring; and n is 1 or 2;

; and R ₄ is hydrogen, C1-6 alkoxy or halogen. 8. A compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein R ₃ is hydrogen, C1-6 alkoxy, or alkoxy corresponding to the formula -O-X-Y, where: X is linear C1-6 alkylene; and Y is a benzothiophene, pyridine or a substituent corresponding to the general formula (II)

Z is hydrogen, C1-6 alkoxymethyl, or a substituent according to the following general formulas (III), (IV), (V) or (VI):

each of Z ₁ and Z ₂ is C1-6 alkyl, or Z ₁ and Z ₂ are connected to each other to form, together with the nitrogen atom to which they are attached, a 5- or 6-membered ring; and n is 1 or 2;

, and R ₄ is hydrogen. 9. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein the compound or salt is selected from the following: 3-[4-(5-Methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione, 3-[4-(5-bromo-4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione, 3-[4-(4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione, 3-{4-[4-(benzyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidin-2,6-dione, 3-(4-{4-[4-(methoxymethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione, 3-{4-[4-(4-{[(2S,6R)-2,6-dimethylmorpholino]methyl}benzyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl} piperidine-2,6-dione, 3-(4-{4-[4-(pyrrolidin-1-ylmethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidin-2,6-dione, 3-(4-{4-[4-(piperidin-1-ylmethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidin-2,6-dione, 3-(4-{4-[4-(2-morpholinoethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione, 3-[4-(4-{4-[(dimethylamino)methyl]benzyloxy}thiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione and 3-{4-[4-(benzo[b]thiophen-2-ylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidin-2,6-dione, and their acid addition salts. 10. The compound according to claim 1 or its salt, where the compound or salt is selected from the following: 3-[4-(5-Methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione, 3-[4-(4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidin-2,6-dione, 3-(4-{4-[4-(methoxymethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione, 3-{4-[4-(4-{[(2S,6R)-2,6-dimethylmorpholino]methyl}benzyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl} piperidine-2,6-dione and 3-(4-{4-[4-(piperidin-1-ylmethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidin-2,6-dione. 11. A drug having an activity of suppressing the production of TNF-α, containing the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 12. The drug according to claim 11, where the drug is an agent for suppressing the production of TNF-α. 13. The drug of claim 11, wherein the drug is a prophylactic or therapeutic agent against an inflammatory disease, an autoimmune disease, or a hematological malignancy. 14. The medicament of claim 13 wherein the autoimmune disease is rheumatoid arthritis, Crohn's disease or ulcerative colitis. 15. The medicament of claim 13, wherein the hematological malignancy is leukemia, malignant lymphoma, or multiple myeloma. 16. The medicament of claim 13 wherein the hematologic malignancy is multiple myeloma. 17. The medicament of claim 13, wherein the hematological malignancy is lymphoma malignant. 18. The medicament of claim 13, wherein the hematological malignancy is leukemia. 19. The medicament of claim 15, wherein the malignant lymphoma is non-Hodgkin's lymphoma. 20. The medicament of claim 19, wherein the non-Hodgkin's lymphoma is a neoplasm of lymphoid progenitors or a neoplasm of mature B cells. 21. A pharmaceutical composition having an activity of suppressing the production of TNF-α, containing the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier. 22. A method of suppressing TNF-α production in a mammal, comprising administering an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, to the mammal. 23. A method of preventing or treating an inflammatory disease, an autoimmune disease, or a hematological malignancy, comprising administering a prophylactically or therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, to a mammal in need of its administration. 24. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of an inflammatory disease, an autoimmune disease, or a hematological malignancy.